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In order to develop orally active CCR5 antagonists, we investigated 1-benzoxepine derivatives containing new polar substituents, such as phosphonate, phosphine oxide or pyridine N-oxide moieties, as replacements for the previously reported quaternary ammonium moiety. Among these compounds, the 2-(alpha-hydroxybenzyl)pyridine N-oxide 5e exhibited moderate CCR5 antagonistic activity and had an acceptable pharmacokinetic profile in rats. Subsequent chemical modification was performed and compound (S)-5f possessing the (S)-configuration hydroxy group was found to be more active than the (R)-isomer. Replacement of the 1-benzoxepine ring with a 4-methylphenyl group by a 1-benzazepine ring with a 4-[2-(butoxy)ethoxy]phenyl group enhanced the activity in the binding assay. In addition, introduction of a 3-trifluoromethyl group on the phenyl group of the anilide moiety led to greatly increased activity in the HIV-1 envelope-mediated membrane fusion assay. In particular, compound (S)-5s showed the most potent CCR5 antagonistic activity (IC(50)=7.2 nM) and inhibitory effect (IC(50)=5.4 nM) in the fusion assay, together with good pharmacokinetic properties in rats.

In order to introduce 2-pyridyl group into the 9 position of 1, 1-disubstituted quinolizidine, N-benzoyloxypyridinium chloride (1) was treated with 9-dehydro-1-oxoquinolizidine (3), dehydro-1-ethoxycarbonyl-1-hydroxyquinolizidine (13) and 9-dehydro-1, 1-ethylenedioxyquinolizidine (16) in dichloromethane, followed by reduction of the reactants with sodium borohydride in anhyd. ethanol. Although reactions with 3 and 13 gave no satisfactory result, that with 16 afforded the expected 1, 1-ethylenedioxy-9-(2-pyridyl)-quinolizidine (18) in 17% yield together with dehydro-1, 1-ethylenedioxy-x-(2-pyridyl)-quinolizidine (19). Other observations encountered in reactions of 1 with 3 or 13 as well as in transformation of 2 into 13 and 16 were also described in some detail.

In the 1, 3-dipolar cycloaddition reaction of 3-methylpyridine N-oxide with phenyl isocyanate, spectroscopic evidence indicates that phenyl isocyanate forms charge-transfer complexes with both pyridine N-oxide and aromatic solvents such as pyridine. In connection with the charge-transfer complex formation, the solvent effect on the site selectivity was investigated. The most prominent solvent effect was observed in the reaction using 3-methylpyridine as a solvent. The equilibrium constants for the interaction of 3-methylpyridine N-oxide with phenyl isocyanate in several solvents were found to be quite large, indicating that the reaction mixtures favor complex formation. The proton nuclear magnetic resonance (1H-NMR) spectra of the mixtures show a high field shift of the methyl signal of 3-methylpyridine N-oxide due to charge-transfer complexation. Based on these results, the structure and role of the complexes are discussed.

The 1, 3-dipolar cycloaddition reactivity of pyridine N-oxides to phenyl isocyanate was calculated by the MINDO/3 MO method using the perturbation equation derived by Klopman and Salem. The calculation did not predict the low reactivity of acceptor substituted pyridine N-oxides. On the basis of the calculation data, the general 1, 3-dipolar cycloaddition reactivity of pyridine N-oxides towards various phenyl isocyanates is discussed in terms of the concept of cyclic conjugation. The aromaticity of the pyridine N-oxide may play an important role in determination of the reactivity. In connection with the cycloaddition, the 1, 5-sigmatropic rearrangement of the primary cycloadducts and the pyrolytic reaction behavior of the 2, 3-dihydropyridine derivatives formed by a 1, 5-sigmatropic shift from the primary adducts are discussed on the basis of the MINDO/3 calculation data.

The 1-oxido-4-pyridyl radical generated by the reaction of 4-aminopyridine 1-oxide with amyl nitrite reacted smoothly with aromatic hydrocarbons, including five-membered heterocycles, i.e. thiophene, furan and pyrrole, to give the arylated products when acetic acid was used as the solvent. The relative rates of reaction with the 1-oxido-4-pyridyl radical indicated that this radical is electrophilic, and this finding was supported by a comparison of molecular orbital energy levels. 2-Aminopyridine 1-oxide also undergoes a similar reaction.

Pericyclic reactions of 3, 5-dimethylpyridine N-oxide to N-phenylmaleimides were investigated. The exo 1 : 1 cycloadducts were formed stereoselectively as primary products. The reaction behavior is discussed in terms of frontier molecular orbital theory, based on kinetic and MO calculation data.

To provide additional evidence for the concerted mechanism postulated for the 1, 3-dipolar cycloaddition reaction of pyridine N-oxides with phenyl isocyanates, kinetic studies on the cycloaddition reactions were conducted in a variety of solvents. The cycloaddition showed low sensitivity to the ionizing power of the medium, indicating that it proceeds by a mechanism which involves very little change in charge separation between the ground state and the transition state. The observed cycloadditivity and site selectivity are discussed in terms of the following controlling factors based on MINDO/3 calculations : HOMOLUMO control, secondary orbital interaction, steric interaction, dipole-dipole interaction and charge-transfer complexation.

Preparations of pyridine N-oxide (7a) and N-aminopyridinium chloride (10a) by ring opening of a quaternary pyridinium salt and successive recyclization were investigated, and the following methods established. Treatment of N-(2, 4-dinitrophenyl) pyridinium chloride (5a) with hydroxylamine, followed by refluxing the resulted 5-(2, 4-dinitroanilino)-2, 4-pentadienal oxime (6a) in dioxane-water (4 : 1) gave pyridine N-oxide (7a) in 87% yield from pyridine. Refluxing a mixture of N-(2, 4-dinitrophenyl) pyridinium chloride (5a) and hydrazine hydrate in dioxane-water (4 : 1) after being kept overnight at room temperature, gave N-aminopyridinium chloride (10a) in 50% yield from pyridine. The methods were proved to be applicable to conversions of β-, γ-picoline and 3, 5-lutidine into the corresponding N-oxides and N-amino derivatives.

Reactions of N-dimethylaminophenylnitrones, having either pyridine or quinoline ring, as α-substituent, with six sorts of reagent such as SO2, P (OPh) 3, PO (OPh) 3, were examined. The observation that the deoxygenation and the rearrangement reaction of these nitrones were competitive each other confirmed the conclusion that-I effect of the heteroaromatic ring was responsible for deoxygenation and that +M effect of Noxide group might cause rearrangement.

Dimerization reactions of six π-rich N-heteroaromatic compounds (2-7) and five xanthine derivatives (8-12) in the presence of platinated palladium-carbon (Pd-Py/C) catalyst were investigated. N-Methylimidazole (2), benzimidazole (4) and N-methylbenzimidazole (5) condensed dehydrogenatively to afford the corresponding symmetric dimers when heated in the presence of Pd-Pt/C catalyst and pyridine N-oxide (1). On the other hand, imidazole (3), pyrazole (6) and N-methylpyrazole (7) did not dimerize under the same conditions. The same reactions using caffeine (10), 1, 7-dimethylhypoxanthine (9) gave the corresponding dimers.

4-Pyridoxyacetic acid, a substance to be used in a study on plant growth substances, cannot be obtained by reacting 4-hydroxypyridine with chloroacetic acid or ethyl diazoacetate, only the N-(4-pyridonyl) acetate or its ester being formed. The desired compound was synthesized from 4-hydroxypyridine 1-oxide by converting the N-oxide with chloroacetic acid into N-(4-pyridonyl) oxyacetic acid and by heating this acid with a solution of ethyl diazoacetate in petroleum ether. Discussion is made on the mechanism of this process by other routes used for its preparation.

The reactions of pyridine N-oxide (1) with hydroxypyrimidine derivatives (2-7) in the presence of platinated palladium-carbon (Pd-Pt/C) catalyst were studied. 5-Hydroxypyrimidine (2), 4-hydroxypyrimidines(3 and 4) and 1-methyl-2-pyrimidinone (6) gave the corresponding dimers and 2-pyridyl derivatives by this condensation with high regioselectivity at the dehydrogenative position, while 2-hydroxypyrimidine (5) gave only the 2-pyridyl derivative. 2, 4-Dihydroxypyrimidine (7) did not react under similar reaction conditions. All products obtained these reactions are new compounds.These dimerization reactions may be useful for the synthesis of the dimers of N-heteroaromatic compounds.