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Reaction of 4-alkoxyquinazolines (II) with perphthalic acid afforded, besides the objective 4-alkoxyquinazoline 1-oxides (III), 2-hydroxy-4-alkoxyquinazoline 1-oxides (IV) as a by-product, formed by oxidation of 2-position. (III) was hydrolyzed to 4-hydroxyquinazoline 1-oxide (V), methylated, and catalytically reduced to 3-methyl-4-quinazolone (VII), whose identification by admixture with an authentic specimen proved the original compounds to be the 1-oxide. The structure of (IV) was also proved by its methylation followed by catalytic reduction to form 4-alkoxy-2-quinazolone (IX).

Since the reaction of sodium methoxide with 4-chloro-6-methylpyrimidine-2-carbonitrile afforded 2, 4-dimethoxy-6-methylpyrimidine, the cyano group in 2-and 4-positions of the pyrimidine ring is fairly active to nucleophilic reagents. Reaction with 2-cyanopyrimidine derivatives showed that the substitution of cyano group with alkoxide ion decreased in the order to primary, secondary, and tertiary alkyls. This reaction did not take place when the alkoxide ion was replaced with phenoxide or thiophenoxide ion, forming acid amide alone. Application of sodium ethoxide to 2-cyanoquinoline, 4-cyano-quinoline, and 4-cyanoacridine failed to produce any ethoxylated derivatives.

The reaction of diketene with amino-methylpyridines (Ia-i) was investigated, and the products were identified by the mass spectroscopic study. The reaction of 2-(Ia) and 3-amino-methylpyridines (Ib, d, f, h) with diketene gave the pyridone derivatives (IIIa, b, d, f, h), but 4-amino-methylpyridines (Ic, e, g, i) afforded the pyrone derivatives (IVc, e, g, i). The mass spectrum of III showed the characteristic peaks at m/e 243, 215, 187 and 175, and in the case of IV the strong peaks were observed at m/e 151, 108, 67 and 43. Each fragmentation pathways were discussed.

Several 4-alkoxy-6-methylpyrimidines were prepared and they were derived to N-oxides by the application of hydrogen peroxide in glacial acetic acid solution or monoperphthalic acid in ether. These were all N-monoxides and were derived to corresponding 4-alkoxy-6-methylpyrimidine-2-carbonitrile by the Reissert reaction. The nitriles so obtained were converted to the corresponding acid amides by treatment with alkaline hydrogen peroxide. Treatment of 4-methoxy-6-methylpyrimidine-2-carbonitrile with sodium methoxide afforded 2, 4-dimethoxy-6-methylpyrimidine, confirming the position of cyano group.

Reaction of diketene with 2-aminopyridine (Ia), 2-amino-4-methylpyridine (Ib), and 2-amino-3-methylpyridine (Ic) gave 2-methyl-4H-pyrido [1, 2-a] pyrimidin-4-one (Ma), 2, 8-dim.ethyl-4H-pyrido [1, 2-a] pyrimidin-4-one (IIIb), and 2, 9-dimethyl-4H-pyrido [1, 2-a]-pyrimidin-4-one (IIIc), respectively. Isomeric 2-one derivatives, such as 4-methyl-2H-pyrido [1, 2-a] pyrimidin-2-one (IVa) and 4, 8-dimethyl-2H-pyrido [1, 2-a] pyrimidin-2-me (IVb), were prepared by reaction of α-bromccrotonic acid with Ia and Ib, respectively. The differences were sufficiently great to permit mass, nuclear magnetic resonance, infrared and ultraviolet spectral data in a distinction of the structures between the 4-one (III) and 2-one derivatives (IV).

Reactivity of cyano group in 4-position of 2, 6-dimethylpyrimidine-4-carbonitrile was examined. This compound behaves like ordinary nitriles in forming 4-acetyl compound with methylmagnesium bromide, 4-carboxylic acid ester with dehydrated alcohol and hydrogen chloride, and 4-acid amide with alkaline hydrogen peroxide. However, it showed specificity in undergoing substitution with methoxyl ion to form 4-methoxy compound. The ester or acid amide obtained by such reaction was reacted with hydrazine hydrate to afford 2, 6-dimethylpyrimidine-4-carbohydrazide. Condensation with few other aldehydes was also carried out.

The reaction of β-aminocrotonamide (V) with ketene afforded α-acetyl-β-aminocrotonamide (VII). When the reaction was carried out in the presence of triethylamine or pyridine, α-acetyl-β-acetylaminocrotonamide (VIII) was obtained. Heating of the diacetyl compound (VIII) with sodium hydroxide gave 5-acetyl-2, 6-dimethyl-4 (1H)-pyrimidone (IX) in good yield. Similarly, the reaction of β-amino-N-methylcrotonamide (XII) with ketene afforded α-acetyl-β-acetylamino-N-methylcrotonamide (XV) and 5-acetyl-2, 3, 6-trimethyl-4 (1H)-pyrimidone (XIV). On the other hand, the treatment of β-amino-N, N-dimethylcrotonamide (XIII) with ketene resulted in the formation of a resinous product. The reaction of V or XII with diketene yielded 3-acetyl-4-hydroxy-6-methyl-2 (1H)-pyridone derivatives. The reaction of XIII with diketene gave only nitrogen free compounds.

Catalytic reduction of 4-benzyloxy-6-methylpyrimidine 1-oxide in methanol over palladium-carbon resulted in the formation of 6-methyl-4-pyrimidinol via 4-hydroxy-6-methylpyrimidine 1-oxide. The use of Raney nickel as a catalyst in this case afforded 4-benzyloxy-6-methylpyrimidine and this is a new type of reaction not recorded in past literature.

Reaction of anionoid reagents with 2-phenoxy-6-methylpyrimidine (IV) and its N-oxide (III) was carried out to examine the reactivity of the phenoxyl in 4-position. It was found that there is no great difference in the reactivity of the phenoxyl group between (III) and (IV) but the phenoxyl in these compounds were substituted more easily than that in 4-phenoxypyridine. During the course of this reaction, 4-phenylthio-(VII), 4-piperi-dino-(VIII), and 4-morpholino-6-methylpyrimidine 1-oxide (IX), which cannot be prepared by the direct N-oxide formation reaction of the corresponding tertiary bases, were obtained.

Objective Dopamine supersensitivity psychosis (DSP) is considered to be one cause of treatment-resistant schizophrenia (TRS). The authors investigated the efficacy of risperidone long-acting injections (RLAI) in patients with TRS and DSP. Method This is a multicenter, prospective, 12-month follow-up, observational study that included unstable and severe TRS patients with and without DSP. 115 patients with TRS were recruited and divided into two groups according to the presence or absence of DSP which was judged on the basis of the clinical courses and neurological examinations. RLAI was administered adjunctively once every 2 weeks along with oral antipsychotics. We observed changes in scores for the Brief Psychiatric Rating Scales (BPRS), Clinical Global Impression—Severity of Illness (CGI-S), Global Assessment of Functioning Scale (GAF), and Extrapyramidal Symptom Rating Scale (ESRS) during the study. Of the assessed 94 patients, 61 and 33 were categorized into the DSP and NonDSP groups, respectively. Results While baseline BPRS total scores, CGI-S scores and GAF scores did not differ, the ESRS score was significantly higher in the DSP group compared with the NonDSP group. Treatment significantly reduced BPRS total scores and CGI-S scores, and increased GAF scores in both groups, but the magnitudes of change were significantly greater in the DSP group relative to the NonDSP group. ESRS scores were also reduced in the DSP group. Responder rates (≥ 20% reduction in BPRS total score) were 62.3% in the DSP group and 21.2% in the NonDSP group. Conclusions It is suggested that DSP contributes to the etiology of TRS. Atypical antipsychotic drugs in long-acting forms, such as RLAI, can provide beneficial effects for patients with DSP. Clinical trials registration: UMIN (UMIN000008487).

In the palladium-catalyzed cross-coupling reaction of halopyrimidines with terminal acetylenes, 2- and 4-chloropyrimidines can be used as starting compounds, though their reactivity is inferior to that of 2- and 4-iodopyrimidines. The conversion of the 2- and 4-alkynylpyrimidines thus obtained into the corresponding pyrimidinylmethyl ketones was successfully achieved by consecutive treatment with piperidine and oxalic acid dihydrate.

2, 6-Dichlorophenolindophenol (DCIP)-dependent polyethylene glycol (PEG) dehydrogenase activity was found in the particulate fractions of cell-free extracts prepared from PEG-utilizing bacteria ( Pseudomonas and Flavobacterium species). This result suggested that PEG dehydrogenase is linked to the respiratory chain of each bacterium and that the enzyme plays a major role in the aerobic metabolism of PEG. Enzyme activities were strongly inhibited by 1, 4-benzoquinone. No metal ion was indispensable for the enzyme activities. Enzyme activities of PEG-utilizing bacteria were induced by PEG except for the activity of PEG 4000-utilizing Flavobacterium sp. no. 203 which had a constitutive enzyme. Although PEG-utilizing bacteria had different growth substrate specificities toward PEGs 200–20,000, their PEG dehydrogenases oxidized the same molecular wt. range of PEGs (dimer-20,000). Cell-free extracts of PEG 400-, 1000- or 4000-utilizing bacteria oxidized PEG 6000 and 20,000 though these bigger PEGs could not be utilized as the sole carbon and energy sources by the bacteria. Methanol, ethylene glycol and glycerol were not or only barely dehydrogenated by all the enzyme preparations.

The arylation of 2-, 4-, and 5-halopyrimidines with aryltributylstannanes in the presence of dichlorobis-(triphenylphosphine)palladium was investigated with successful results. The reaction can be expanded to the synthesis of 2-, 4-, and 5-vinylpyrimidines with generality. The site-selectivity of the reaction for 4, 5-dihalopyrimidines is also described.

In the catalytic reduction of hydroxamic acid and compounds possessing hydroxyl adjacent to the N-oxide group and forming a hydroxamic acid-type structure, Raney nickel catalyst was found to act specifically in severing the nitrogen-oxygen bond. 2-Hydroxyquinoline 1-oxide, 4-methoxy-and 4-ethoxy-2-hydroxyquinazoline 1-oxide, and benzohydroxamic acid were deoxygenated forming 2-hydroxyquinoline, 4-methoxy- and 4-ethoxy-2-hydroxyquinazoline, and benzamide. In 4-benzyloxy-2-hydroxyquinazoline 1-oxide, the reduction of benzyloxyl group preceded the reduction of N-oxide group and 2, 4-dihydroxyquinazoline was formed via its 1-oxide compound.

The influence of triphenylphosphine, used as a ligand, on the palladium-catalyzed cross-coupling reaction of iodopyrimidines with olefins such as ethyl acrylate, acrylonitrile, and styrene was investigated. In general, the addition of triphenylphosphine was concluded to retard the reaction in the pyrimidine series. The effect of triphenylphosphine in the monoazine series is also discussed.

An enzyme fraction which catalyzes the reduction of trans-2-enoyl-coenzyme A (trans-2-enoyl-CoA) to the corresponding saturated acyl-CoA derivative was separated from Escherichia coli (E. coli) extracts. The enzyme utilized reduced nicotinamide adenine dinucleotide phosphate (NADPH) as a sole electron donor for the reduction of substrates, and it acted on acyl-CoA substrates, but not on acyl-carrier protein esters. Therefore, the name NADPH-dependent trans-2-enoyl-CoA reductase was proposed for this enzyme. The reductase was stable at around pH 7-8, and was active over a wide pH range between 6 and 9. It had a functional thiol group and was readily inhibited by thiol reagents such as p-hydroxymercuribenzoic acid, and by cupric and some other metal ions. The enzyme was induced when E. coli cells were cultured in a medium containing oleic acid. These results suggest that this reductase does not participate in the de novo synthesis of fatty acids but is a new enzyme, although its physiological role is uncertain at the present stage.

The reflectance and structure changes of iridium oxide films by reduction were investigated in an attempt to apply the films to optical data storage media. The films were prepared by the thermal oxidation of iridium-carbon composite films. The films were easily reduced by heating them in 5% H/sub 2/ in Ar at temperatures in the range 100/sup 0/-300/sup 0/C. When the films were reduced, the particles size of Ir metal and the reflectance of the films increased with an increase in the reducing temperature. The reduced films were stable against oxidation at temperatures of 250/sup 0/C or higher. Optical writing on the films was carried out with an argon laser at 0.84W power. The writing mechanism was based on changes in the film's optical properties caused by laser-induced reduction.

A series of 2-(2-aminoethyl) pyridines derived by the modification of the amine moiety in betahistine, 2-(2-methylaminoethyl) pyridine, was synthesized and evaluated for antivertigo action in terms of inhibitory activity against spontaneous nystagmus in cats. The structure-activity relationships between the amine moieties and antivertigo activities were investigated. The effects of substituents on the phenyl ring of the 4-phenylpiperazine moiety were investigated by means of quantitative regression analysis using various physicochemical parameters. The following equation gave the best correlation. log 1/ID30=-0.417 (±0.322) π+0.166 (±0.048) MR-1.473 (±0.237) (n=15, s=0.239, r=0.910, F212=28.887). In this series of compounds, 1-(2-methoxyphenyl)-4-[2-(2-pyridyl) ethyl] piperazine, 1-(2-methoxyphenyl)-4-[2-[2-(6-methyl) pyridyl] ethyl]-piperazine, and 1-(2-methoxyphenyl)-4-[2-[2-(5-ethyl) pyridyl] ethyl] piperazine were found to show more potent activity than betahistine. Thus, the 4-(2-methoxyphenyl) piperazine group was found to be the most effective amine moiety for activity against spontaneous nystagmus.

The condensation of 2, 4 (2, 6)-dimethylpyrimidines (7a-c), but not 6-methoxy-2, 4-dimethylpyrimidine (7d), with benzaldehyde in the presence of zinc chloride occurred at the 4 (6)-methyl group predominantly. In contrast, the reaction of 7d under the same conditions gave 6-methoxy-4-methyl-2-styrylpyrimidine (17) as the main product. Similar site-selectivity in the oxidation of the dimethylpyrimidines with selenium dioxide was found.