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The three-dimensional structure of 4'-azidothymidine has been determined for the solid state and in solution. X-ray crystal analysis indicates the presence of two independent molecules (A and B) having the following conformational parameters: Phase angles, PA = 13.7 degrees, PB = 12.6 degrees (C3'-endo envelope); puckering amplitude psi mA = 32.4 degrees, psi mB = 37.2 degrees; glycosyl torsion angle chi A = -88.2 degrees, chi B = -71.2 degrees; 4'-5' torsion angle gamma A = 58.5 degrees, gamma B = 36.0 degrees. The solution conformation was determined from NMR coupling constants in D2O. Analysis using the computer programs PSEUROT and DAERM yielded phase angles (P) of 53.2 degrees (C4'-exo envelope) (major conformer) and 63 degrees (C4'-exo envelope), respectively, with corresponding puckering amplitudes (psi m) of 34.9 degrees and 45.8 degrees. A gated 13C NMR experiment was used to determine the 1H-13C vicinal coupling constants used to calculate the solution glycosyl torsion angle (chi) to be either -80 degrees or -160 degrees and a 4'-5' torsion angle, gamma, of ca. 180 degrees. These studies show that 4'-azidothymidine is conformationally exceptional among the antiretroviral nucleosides both as a solid and in solution. The C3'-endo (northern) conformation determined by X-ray crystallography is rare among HIV-inhibitory nucleosides which usually exist in the solid state in a southern conformation. The solution structure is even more peculiar in that it exists in the extremely rare 4'-exo envelope conformation.
Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
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