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The pyridines 5, obtained by dehydrogenation of the 4-(2-nitrophenyl)-1,4-dihydropyridine lactones 4, give the tetracycles 6 and 7 by reduction of the nitro group with zinc/ammonium chloride followed by ring closure. Irradiation of the compounds 4 with UV-A light leads to the 4-(2-nitrosophenyl)pyridines 8. During the reaction of 8 with conc. hydrochloric acid the nitroso group cyclizes with the 5-acyl group yielding the chloro substituted tetracycles 9 and 10. The hydroxamic acids 6 and 9 are deoxygenated by phosphorus trichloride to yield the lactames 11, while O-acetylation with acetic anhydride affords 12. Phosphorus trichloride reduces the N-oxides 7 and 10 to the bases 13. Using the reaction with acetic anhydride the acetates 14 are formed by Boekelheide-transformation. Alcaline saponification of 14 gives the alcohols 15.
The reaction of 2-nitrobenzaldehyde with methyl propiolate and ammonium acetate in acetic acid yields 2,6-dinor-nifedipine (1a) and the isomeric rac. 1,4-dihydropyridine (DHP) 1b. The DHP 1 are dehydrogenated both chemically and by anodic oxidation using a rotating platinum electrode (RPE) by means of differential pulse voltammetry (DPV) affording the corresponding pyridines 2a, b. Compound 1a is more stable, while compound 1b is less stable than nifedipine. Irradiation of the DHP 1 with UV-A light forms the nitrosophenyl-pyridines 3, which cyclize after addition of conc. hydrochloric acid to yield the chloro substituted hydroxamic acids 4a, b. The hydroxamic acids 4c, d are obtained treating 2a, b with zinc in acetate buffer pH 4.6. The hydroxamic acids 4b, d demonstrate only a moderate inhibition of 5-lipoxygenase (5-LOX) of human whole blood compared with the activity of the reference compound zileutone. The formation of 15-HETE is also inhibited. Compound 4a reduces the activity of cyclooxygenase. The lactames 5, obtained from the hydroxamic acids 4 by desoxygenation with phosphorus trichloride, react with phosphoryl chloride to give compounds 6, representing educts for potential agents against malaria.
Absorption, distribution and excretion of T-3262 were studied in rats and mice after oral administration of 14C-T-3262. The obtained results are summarized as follows. 1. 14C-T-3262 was absorbed from the upper small intestine such as duodenum in rats. 2. Serum levels of radioactivity in rats reached the highest concentration at 1 hour after an oral administration, then gradually diminished. 3. Urinary excretion was 35% and 42% of the dosed radioactivity in rats and mice, respectively, and fecal excretion was about 65% and 56% of the dosed radioactivity in rats and mice, respectively. 4. Biliary excretion in rats was about 27% of the dosed radioactivity after an oral administration of 14C-T-3262, and a half amount of excreted radioactivity was reabsorbed from the intestine. 5. Radioactivity was distributed the most into the kidney and the liver among all organs other the stomach and the intestine. Radioactivity was widely distributed into other organs such as spleen, adrenal, pancreas, lung, heart and thymus. But the distribution of radioactivity into the brain was little. 6. The distribution of 14C-T-3262 was also studied with whole body autoradiography in normal male mice and pregnant mice. The radioactivity was distributed widely to whole tissues except brain, spinal cord and eye ball. In pregnant mice, radioactivity levels in the fetuses were the same as the blood level of the mother mice. 7. The binding rate of 14C-T-3262 to rats and mice serum proteins was 63-66%. 8. Urinary and fecal excretion patterns of radioactivity in mice after multiple oral administration of 14C-T-3262 for 10 days were similar to those after a single administration. This result suggests that T-3262 did not accumulate in body. 9. After oral administration of 14C-T-3262 to nursing rats, the secreted radioactivity level in the milk was higher than the blood level.