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Syntheses are reported for three metabolites (2-4) of timolol (1) formed by oxidative metabolism of the morpholine ring. GLC-MS comparisons are presented which establish that the two metabolites whose structures were previously in question are identical with their synthetic counterparts 2 and 3. In 2, metabolic oxidation of the 4-morpholinyl group of 1 had occurred at the carbon next to oxygen to give the 2-hydroxy-4-morpholinyl moiety, whereas in 3, the morpholine of 1 has been oxidized one step further and then ring opened to produce the N-(2-hydroxyethyl)glycine substituent. Biological testing of synthetic samples of the three major metabolites from human urine (3, 4, and 6) indicated that only 4, in which the morpholine moiety has been degraded to a 2-hydroxyethylamino group, had significant beta-adrenergic blocking activity (one-seventh that of timolol in anesthetized dogs).

Reaction of Excited Oxygen Atoms with N20 1341 trosoethane reaction,29 ky determined by this procedure is actually a lower limit.The lower limit found for ky indicates that ( 7) is a very fast reaction and that therefore trifluoronitrosomethane is an effective scavenger for trifluoromethyl radicals. The scavenging sequence in the trifluoromethyl radical-nitric oxide system is clearly seen in Figures 5 and 6. Thus, the behavior of m/e 30 and 130 with time shows that (6) occurs exclusively until the nitric oxide has been so depleted and the trifluoronitrosomethane so abundant that (7) replaces (6) as the exclusive fate of the trifluoromethyl radicals. The onset of m/e 119 and 304 at about 7 min when the trifluoronitrosomethane has been consumed shows that only after this time can the uninhibited photochemi-cal decomposition mechanism via eq 2-5 take place. The almost complete inhibition of reactions 2-5 by ( 7) indicates that trifluoronitrosomethane is a more effective scavenger for trifluoromethyl radicals than is nitrosomethane for methyl radicals28 or nitrosoethane for ethyl radicals.29 Acknowledgment. This work was supported in part by the United States Atomic Energy Commission under Contract No. AT(11-1)-3416 and in part by the Petroleum Research Fund, administered by the American Chemical Society. We also thank the National Science Foundation for providing funds to assist in the original purchase of the time-of-flight mass spectrometer.

Abstract-Combined gas chromatography-mass spectrometry and isotope labeling techniques have been employed to demonstrate that the carboxamide nitrogen atom in 2-car boxamido-5-isopropoxycarbonylaminobenzimidazole, a metabolite of 2-thiazolyl-5-isopropoxycarbonylaminobenzimidazole (cambendazole), is derived wholly from the parent drug. ["N] Thiazole-labeled cambendazole was administered to a rat and the metabolite isolated from urine. Trideutero-2-carboxamido-5-isoprop0xycarbonylaminobenzimidazole was employed as a carrier to isolate the metabolite in sufficient purity for isotope ratio measurements using multiple ion detection. The metabolite was converted to its tetramethyl derivative by on-column reaction with trimethylanilium hydroxide to permit satisfactory gas chromatography.

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