The first synthesis of 2-amino-α-phenylbenzylideneaminoacetonitriles (IV) was achieved by an amine exchange reaction between Schiff bases (II) and aminoacetonitrile hydrogensulfate (III) in the presence of 2-methylimidazole. Compounds (IV) were cyclized to 2-amino-1, 4-benzodiazepine derivatives (V) in a good yield using potassium hydroxide in ethanol or dry hydrogen chloride in methanol or ethanol. When an N-substituted analog of IV was emrloyed in this reaction, a new type of derivative, 2-imimo compound (VII), was obtained. Both V and VII were hydrolyzed easily and selectively to their corresponding 1, 4-benzodiazepin-2-ones when their acid salts were heated in methanol. Certain geometrical isomers of IV were isolated and their isomeric structure was determined by infrared, ultraviolet and nuclear magnetic resonance spectra. Similarly, 2-amino-7-chloro-5-methyl-3H-1, 4-benzodiazepine (XIII) was synthesized by cyclization of 2-amino-5-chloro-α-methylbenzylideneaminoacetonitrile (XII) with methanolic potassium hydroxide.

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Derivatives of 2-amino-α-phenylbenzylideneaminoacetal (II) were prepared by an amine exchange reaction of Schiff bases (I) of 2-aminobenzophenone with aminoacetal in the presence of an acid catalyst. Cyclization of II with ethanolic hydrogen chloride under mild conditions gave 2, 3-dihydro-2-ethoxy-1H-1, 4-benzodiazepine derivatives (III) which were easily hydrolyzed to their corresponding 2-hydroxy-1, 4-benzodiazepines (IV). Chromium oxidation of IV afforded the known 1, 4-benzodiazepin-2-ones (V). When the cyclization reaction was carried out under reflux conditions, 3-aminoquinoline derivatives (VI and VII) were obtained as a result of an intramolecular rearrangement.

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Nicotinic acid and isonicotinic acid, being an isomer of picolinic acid, were found to form insoluble and fairly stable metal complexes with various metals. These complexes had 2 : 1 ratio of the ligand to the metal, similar to chelates of picolinic acid, and nicotinic acid also formed cation complexes with cobalt, iron, and manganese. With reference to picolinic acid -metal chelates, the metal complexes of nicotinic and isonicotinic acids were considered to exist in a succinonitrile type structure from elemental, infrared spectral, and reflectance spectral analyses.

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3-Chloro-2-chloromethylacrylonitrile (5), 2-chloromethyl-2, 3-dichloropropionitrile (7), and 3-chloro-2-dichloromethylpropionitrile (12) reacted smoothlyl with acetamidine in benzene or methanol to give 2, 7-dimethyl-5, 6-dihydropyrimido [4, 5-d] pyrimidine (17), which was hydrolyzed to 4-amino-5-aminomethyl-2-methylpyrimidine, an important intermediate in the thiamine synthesis. The chlorocompounds (5, 7, 12) were synthesized by the (1) photochlorination of monochloromethacrylonitriles, (2) photochlorination of mono- and di-chloroisobutyronitriles, (8) pyrolysis of sym- and unsym-dichloroacetone cyanohydrin acetates, and (4) dehydrochlorination of trichloroisobutyronitrile and addition of hydrogen chloride to dichloromethacrylonitriles.

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Chlorination of methacrylonitrile (1) was carried out at an elevated temperature in a continuous vapor phase reaction vessel, and the products were isolated by fractional distillation or gas chromatography and their structures confirmed. 3-Chloro-2-chloromethylacrylonitriles (trans and cis isomers, 5a and 5b) which are useful intermediates for the tbiamine synthesis were obtained together with some monochloro derivatives, 3-chloro-2-methylacrylonitrile (2), 2-chloromethylacrylonitrile (3), and 2-chloro-2-chloromethylpropionitrile (4). These monochloro compounds were rechlorinated under a similar condition and dichloro compounds (5a and 5b) were obtained from each monochloro compound.

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Substitution reactions of chloroisobutyronitriles and chloromethacrylonitriles with sodium methoxide in methanol were studied. The reaction products were isolated by fractional distillation or gas chromatography and their structures confirmed. The main products were saturated ether compounds, i. e., β-methoxyisobutyronitriles, but small quantities of unsaturated ethers, i. e., methoxymethacrylonitriles, were formed in certain cases. 2-Chloromethyl-2, 3-dichloropropionitrile (7), and trans-and cis-3-chloro-2-chloromethyl-acrylonitriles (5a, 5b) gave a common end product, 2-dimethoxymethyl-3-methoxypropionitrile (15), but gave different reaction intermediates. Methyl 2-chloromethyl-2, 3-dichloropropionimidate (18) was obtained from 7 and 2-dimethoxymethylacrylonitrile (16) from 5a and 5b.

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In connection with our previous findings that morphine 6-glucuronide and morphine 6-sulfate, although highly polar conjugates, induced potent analgesia, synthesis and analgesic effect of morphine 3-and 6-phosphate were investigated. Chemical synthesis of these phosphate esters was accomplished by utilizing cyanoethylphosphate as a phosphorylation reagent. Analgesic effect of both compounds in mice were found to be about the same order of magnitude as that of morphine when injected subcutaneously or intracerebrally. The tonic extensor convulsion was also observed in mice when morphine phosphate esters were injected intracerebrally (100 μg/body).

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Reaction of 1, 4-naphthoquinone 2, 3-oxide with symmetric disubstituted thioureas in alcohol afforded 2-aryl (alkyl) imino-3-aryl (alkyl) napbtho [2, 3-d] thiazol-2-one-4, 9-diones, which were also obtained by the reaction of 2, 3-dichloro-1, 4-naphthoquinone with symmetric disubstituted thioureas of aromatic amine, though in rather a poor yield in the case of thiorueas of aliphatic amines. 2-Methyl-1, 4-naphthoquinone 2, 3-oxide reacted with symmetric disubstituted thioureas in alcohol to give bis (2-methyl-1, 4-naphthoquinone) 3, 3'-sulfide and symmetric disubstituted ureas. The sulfide was synthesized by the reaction of 3-bromo-2-methyl-1, 4-naphthoquinone with sodium sulfide. 2, 3-Dimethyl-1, 4-naphthoquinone 2, 3-oxide did not react with symmetric disubstituted thioureas.

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The ethereal oxygen in 3-(N, N-disubstituted amino)-1-phenylpropyl phenyl ether (A) was substituted by isosteric groups such as S, NH, CO, CH (OH), and CH₂, and their anticholinergic activities were examined. Diphenylaminobutanols which have CH (OH) group instead of ethereal oxygen showed almost equal anticholinergic activity as the ethereal compounds but other substituted compounds were rather weak in their activity.

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Homologous phenyl 1-phenyl-3-piperidinopropyl ethers, phenyl 1-phenyl-2-piperidinoethyl ethers, phenyl 1-phenyl-4-piperidinobutyl others, and their related compounds were synthesized and their anticholinergic activities were examined. It was thereby found that phenyl 1-phenyl-3-piperidinopropyl ethers having three methylene groups between the nitrogen atom and the oxygen atom in the molecule showed the most potent anticholinergic activities.

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Various substituted 4-cyanopyridines were prepared by the reaction of corresponding substituted 1-(N-methylacetamido) pyridinium salt and potassium cyanide in aqueous, solution. In this reaction, the pyridinium salt which had electron-withdrawal substituent at 3 and/or 5 position provided a mixture of 2- and 4-cyanopyridine derivatives but treatment with potassium cyanide in aqueous solution containing ammonium chloride afforded 4-cyanopyridine derivative alone. The 4-cyanopyridines so obtained were converted into 4-thiocarbonamides whose antituberculosic activity in vitro was tested.(The results are given in Table IV.)

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The reaction of long chain alkyltertiaryamines and epichlorohydrin, in the presence of an organic acid, was followed. In the absence of an organic acid, the reaction in alcohol (ethanol-) or benzene gave 2, 5-(p-dioxyanylene)-bismethylene-bis (trialkylammonium chloride). In the presence of picric acid or sulfonic acid, 3-chloro-2-hydroxypropyltrialkylammonium salts were formed. In the presence of phenols or carboxylic acids, the acid residue was found to combine in ether or ester form to produce 3-phenoxy- or 3-acyloxy-2-hydroxypropyltrialkylammonium chloride. In the presence of acetylacetone, 2-hydroxypropylene-1, 3-bis (trialkylammonium chloride) was formed in 24-29% yield.

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For studies on biological activity, syntheses of 3-substituted 5-methoxy-1-phenylpyrazoles were attempted. N-Substituted 5-methoxy-1-phenylpyrazol-3-ylacetamides (IIa-m) were obtained from (Ia-c). 3-Aminomethyl-5-methoxy-1-phenylpyrazole (V) was synthesized from Ia or IIm by the Schmidt reaction or Curtius reaction. N-Acylmethylamine derivatives (VIa-c, VIIIa-h) and Melubrin-type XIa were obtained from V, but the attempt to prepare N-alkylamine derivatives of V was unsuccesful. 3-Chloromethyl-5-methoxy-1-phenylpyrazole (IX) was synthesized from V, and N-alkylamine derivatives (Xa-m) and sulpyrin type (XIb) were obtained from IX.

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In order to clarify in more detail the cyclization of thioanilide to benzothiazole under the modified Willgerodt-Kindler reaction conditions, 4-picoline was heated with metasubstituted anilines (I) in the presence of sulfur and the reaction also gave thioanilides and one of the two possible benzothiazoles. The latter was proved to have the structure of 5-substituted 2-(4-pyridyl) benzothiazoles (III) by independent synthesis. On the other hand, the expected two isomeric benzothiazoles (III and IV) were obtained from the oxidative cyclization of thioanilides by the modified Jacobson reaction.

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The kinetics of heterogeneous vapor-phase ammoxidation of 4-picoline and 2-picoline was studied over a Cr₂O₃-Al₂O₃ catalyst in a flow system. The reaction was carried out at atmospheric pressure and over the temperature range of 310 to 380°. By this reaction, cyanopyridine was obtained selectively. The reaction rate depended on the partial pressure of picoline and oxygen, but was not affected by that of ammonia, cyanopyridine, or water. Experimental rate data were well interpreted by the Langmuir-Hinshelwood mechanism, where the rate-determining step was the surface reaction between absorbed picoline molecules and absorbed oxygen molecules.

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For the purpose of testing their biological activity, hydroxy group epimers of spiro-[3-hydroxycyclopentane-1, 4'-2', 3'-dihydro-6'-methoxy-2'-methyl-1'H-isoquinoline](IV and V) were synthesized by cyclization of 1-(m-methoxyphenyl)-3-hydroxycyclopentane-methylamines (XXIIIa and XXIIIb), which were obtained from the corresopnding carboxamide derivatives, in the presence of excess formic acid in the Eschweiler-Clarke reaction.

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The structure of pachysantriol, a new triterpenetriol isolated from one of the neutral fractions of Pachysandra terminalis SIEB. et ZUCC (Buxaceae), was investigated and assigned to the formula Ia on the basis of chemical and spectroscopic evidence.

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Absorption, distribution, and metabolic fate of Apiracohl [○!R](Ia, Ib) were studied in rats comparing with hydralazine (II). ¹⁴C-labelled Apiracohl [○!R] (Ia) was synthesized from hydralazine (II) and ethyl chloroformate prepared from CH₃¹⁴CH₂OH and phosgene. Excretion of metabolites of ¹⁴C-labelled Apiracohl [○!R](Ib) was rapid, about 80% of the radioactivity appearing in the urine in 24 hr. The following metabolites were identified in the urine of rats : Unchanged Apiracohl [○!R](trace), its hydroxyderivatives (19.2%), hydralazine (trace), hydralazine glucuronide (16.2%), N-acetylhydralazine (6.9%), hydroxyhydralazine (5.9%), 3-oxo-triazolophthalazine (1.5%), and 3-oxo-triazolophthalazine glucuronide (11.7%). From these results, three metabolic pathways were considered : (1) Hydroxylation of Apiracohl [○!R], (2) decarboethoxylation of Apiracohl [○!R], followed by acetylation, hydroxylation, and glucuronic acid conjugation, and (3) cyclization of Apiracohl [○!R] followed by glucuronic acid conjugation.

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As one of the quantitative analyses of microquantity of medical drugs by atomic absorption spectroscopy, we attempted the synthesis of o- and p-aminobenzenesulfonamide (p-SA) complexes with Zn, Cu, and Ni and found that o-SA binds in a 2 : 1 ratio with Zn, Cu, and Ni, while p-SA complexes indicate the binding ratio of 2 : 1 for Zn and Cu, and 1 : 1 for Ni. From their infrared analyses, the metal in the o-SA metal complexes was assumed to combine with the nitrogen atom in the sulfonamide group and the amino group attached directly to the phenyl group. However, in the case of p-SA-metal complexes with Zn or Cu, the amino group was considered to be the main binding site to the metals, with a weak bonding through the nitrogen atom in the sulfonamide group.

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Silver is quantitatively extracted by shaking with thiothenoyltrifluoroacetone (STTA) solution in carbon tetrachloride from an aqueous solution containing pyridine at pH 6.8±0.1. The silver complex extracted is stable and has an absorption maximum at around 420 nm against a reagent blank. Beer's law holds over the range of 2.5-35 μg of silver/10 ml of organic phase. The molar absorptivity is 5800. The sensitivity is 0.019 μg Ag/cm² for an absorbance of 0.001. The coefficient of variation in precision is 1.9% for 30 μg of silver. The effect of various kinds of co-existing ions was examined. Copper, cobalt, lead, zinc, nickel, mercury, manganese, cadmium, aluminum, iron, gold, sulfide, and cyanide interfere in the determination but the permissible amount of these interfering ions except gold, mercury, sulfide, and cyanide can be increased by adding EDTA solution as a masking agent.

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For the purpose of testing their biological activity hydroxy group epimers of 3-dimethylaminomethyl-3-(m-methoxyphenyl) cyclopentanols (X and XI) were synthesized from 1-(m-methoxyphenyl)-3-hydroxycyclopentanecarbonyl dimethylamide (XVII) and 1-(m-methoxyphenyl)-3-acetoxycyclopentanecarbonyl dimethylamide (XVIII), which were obtained from the corresponding carboxylic acids, by treatment with lithium aluminum hydride in tetrahydrofuran.

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