of these compounds at or above 150 °C gave the previously unknown azides 16 and 17, respectively, identified by their IR spectra at -196 °C and by the fact that they reverted to 14 and 15, respectively, when warmed to -10 to 0 °C [16: IR 2140 (s), 2120 (s), 1350 (s) cm"1. 17: IR 2130 (vs), 2110 (s), 1330 (s) cm"1]. The intensities of the azide absorptions increased with the pyrolysis temperature until ca. 380 °C, when a new and strong absorption at 2000 cm"1 appeared. The latter absorption increased in intensity till ca. 500 °C; the azide absorptions decreased over the same temperature interval. Above 500 °C, the 2000-cm"1 band started disappearing again, and new nitrile absorptions at 2225-2250 cm'1 appeared in its place. The latter absorptions remained unchanged at room temperature, and isolation and chromatographic separation of the material allowed their assignment to the two nitriles 22 and 23, which had been identified previously.4An optimal pyrolysis temperature for the observation of the 2000-cm"1 absorption was found at 490 °C. Under these conditions, only traces of the azides (16 or 17) remained, and only weak bands due to the end products 22 and 23 were present. The spectra recorded at -196 °C, following pyrolysis of either 14 or 15 at 490 °C, were identical, and we therefore assign them to a common intermediate, the carbodiimide 19. When the matrix was warmed to ca. -55 °C, the carbodiimide band at 2000 cm"1 disappeared, and the nitriles 22 and 23 did not appear. Instead, a new compound, C18H12N4, corresponding to a dimer of 19 was isolated. The two dimers formed from 14 and 15 were identical.15These observations are summarized and interpreted in Scheme II. The formation of the common intermediate 19 demonstrates that both 1-isoquinolylnitrene (18) and 2-quinolylnitrene (20) undergo ring expansion under rather mild conditions, i.e., the activation energies cannot be significantly higher than those required for thermolysis of the azides 16 and 17. It would be difficult to interpret the observed spectra in terms of the fused azirines 24 and 25 (Scheme II). These molecules would be expected
MK-0991 (L-743,872) is a potent antifungal agent featuring long half-life pharmacokinetics. The pharmacokinetics of MK-0991 administered intravenously to mice, rats, rhesus monkeys, and chimpanzees is presented. Unique to MK-0991 is its consistent cross-species performance. The range of values for the pharmacokinetic parameters were as follows: clearance, 0.26 to 0.51 ml/min/kg; half-life, 5.2 to 7.6 h; and distributive volume, 0.11 to 0.27 liters/kg. The level of protein binding of MK-0991 was determined to be 96% in mouse and human serum. The compound exhibited high affinities for human serum albumin and at least two lipid components. The rationale for the selection of MK-0991 as a drug development candidate was based on its two- to threefold superior pharmacokinetic performance in chimpanzees over the performance of an otherwise equivalent analog, L-733,560. Once-daily dosing for MK-0991 is indicated by a graphical comparison of levels in the circulations of chimpanzees and mice. In a study of the pharmacokinetics of MK-0991 in mouse tissue, the organs were assayed following intraperitoneal administration. The area under the concentration-versus-time curves (AUC) segregated the tissues into three exposure categories relative to plasma. The tissues with greater exposure than that for plasma were liver (16 times), kidney (3 times), and large intestine (2 times). The exposure for small intestine, lung, and spleen were equivalent to that for plasma. Organs with lower levels of exposure were the heart (0.3 times that for plasma), thigh (0.2 times), and brain (0.06 times). Kinetically, drug was cleared more slowly from all tissues than from plasma, indicating that terminal-phase equilibrium had not been achieved by 24 h. Thus, some measure of accumulation is predicted for all tissues. Single daily doses of MK-0991 should provide adequate systemic levels of fungicidal activity as a result of its long half-life pharmacokinetics, wide distribution, and slowly accumulating concentrations in tissue.
In addition to its potent efficacy in animal models against Candida sp., Aspergillus fumigatus, and Histoplasma capsulatum, the clinical candidate pneumocandin MK-991 (formerly L-743,872) was also extremely potent against Pneumocystis carinii in models of immune-compromised animals. MK-991 was approximately 14 times more potent than the original natural product lead, pneumocandin B0. The 90% effective dose (ED90) of MK-991 for cyst clearance in the rat model for pneumocystis was 0.011 mg/kg of body weight when delivered parenterally for 4 days twice a day (b.i.d.). In a mouse model, under the same experimental parameters, the ED90 was 0.02 mg/kg. MK-991 was also effective orally, with an ED90 for cyst clearance of 2.2 mg/kg against acute infection in rats (b.i.d. for 4 days). Complete prevention of P. cariniidevelopment was achieved in immunocompromised mice at a daily oral dose of 2.25 mg/kg. As reported previously for other pneumocandins and echinocandins, MK-991 selectively prevented the development of P. carinii cysts. When used as a prophylactic agent, neither stage of the organism appeared in the lungs of animals. In response to an acute infection, cysts were eliminated rapidly, while trophozoite forms persisted. Despite good efficacy as an oral agent in murine models, the low oral absorption of this class may limit the use of MK-991 to parenteral therapy.
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