A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has been prepared in an effort to expand the spectrum of activity of this class of antibiotics to include Gram-negative organisms. Pyrrole, pyrazole, imidazole, triazole, and tetrazole moieties have been used to replace the morpholine ring of linezolid (2). These changes resulted in the preparation of compounds with good activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. The unsubstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae = 4 microgram/mL and M. catarrhalis = 2 microgram/mL. Various substituents were also placed on the azole moieties in order to study their effects on antibacterial activity in vitro and in vivo. Interesting differences in activity were observed for many analogues that cannot be rationalized solely on the basis of sterics and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime, and cyano azoles generally led to dramatic improvements in activity against both Gram-positive and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with interesting antibacterial activity in vitro and in vivo. In particular, the 3-cyanopyrrole, 4-cyanopyrazole, and 4-cyano-1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus MICs

The effects of total fasting for 31 ± 10 days followed by re-alimentation with an 800 calorie diet on thyroid function, i.e. T4,T3, rT3, RT3U (resin T3 uptake), and TSH, and on TBG levels in serum were studied sequentially in obese hospitalized patients (N = 18). Additionally, cortisol, growth hormone, prolactin, parathyrin and free fatty acids were followed as hormonal and metabolic parameters, respectively. Further, CBG, transferrin, α2-haptoglobin and complement C'3 were measured as representatives of other serum proteins. Results before fasting: T4, T3,3, TBG, cortisol, CBG, α2-haptoglobin and complement C'3 of the obese patients were elevated when compared with healthy normal weight controls, whereas rT3, T4/TBG ratio, T3/TBG ratio, TSH, cortisol/CBG ratio, growth hormone, prolactin, parathyrin and transferrin of the obese group were normal. RT3U and fT4 index were decreased in the obese patients. Results during fasting: Significant decreases were observed during fasting for the following parameters – T3, TBG, T3/TBG ratio, transferrin, α2-haptoglobin, complement C'3. rT3, T4/TBG ratio, RT3U, fT4 index and FFA increased. T4, TSH response to TRH stimulation, cortisol, CBG, cortisol/CBG ratio, parathyrin, growth hormone and prolactin did not change. Results during re-alimentation: T3, TBG, T3/TBG ratio, TSH response to TRH, transferrin, α2-haptoglobin and complement C'3 increased. Conversely, rT3, RT3U, FFA, cortisol and cortisol/CBG ratio decreased, whereas the other parameters did not change. Conclusions: 1) There is no evidence for primary hypothyroidism in obese patients during prolonged fasting and re-alimentation. 2) The rapid decrease of T3 and increase of RT3U after initiation of fasting are not fully explained by the observed slower decreases in TBG. 3) The alterations of T3, rT3 and RT3U resemble in their kinetics the changes in FFA levels. 4) Fasting reduced the levels of only certain serum proteins, interestingly TBG, transferrin, α2-haptoglobin and complement C'3, all of which, except transferrin, are elevated in obesity. 5) The magnitude of the observed decreases does not suggest any clinically relevant deficiencies in serum proteins. 6) Re-alimentation reverses rapidly all observed changes.

N-[4-[4-(Ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamid e, (E)-2-butenedioate (2:1) salt (ibutilide fumarate, 2E), has been found to have Class III antiarrhythmic activity. In an in vitro rabbit heart tissue preparation designed to evaluate the cardiac electrophysiology of potential antiarrhythmic agents, it selectively prolongs the effective refractory period of papillary muscle. In vivo it increases the ventricular refractory period of the canine heart and prevents the ventricular arrhythmias induced by programmed electrical stimulation 3-9 days after a myocardial infarction. This paper describes the synthesis of 2E and a series of related compounds. The in vitro evaluation of the cardiac electrophysiology of these compounds has allowed us to determine the structural requirements for Class III antiarrhythmic activity in this series. Evaluation of the antiarrhythmic activity of 2E and one of the more potent analogues on the late postinfarction ventricular arrhythmias induced by programmed electrical stimulation of the canine myocardium is also described. This activity is compared with that of the Class III antiarrhythmic agent sotalol. Compound 2E appears to be as effective and 10-30 times more potent than sotalol in this model.

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Treatment of a-hydroxya-phenyl-o-toluidide with phosphorus tribromide afforded a series of 4H-3,l-benzoxazines. These last, when reacted with potassium amide in liquid ammonia, ring contracted to 2,Zdisubstituted 3H-indol-3-01s. The scope of this rearrangement was examined. The indolols on treatment with hot base were found to rearrange to indoxyls. Several of these as well as their N-alkylation products are described.In the course of an investigation of the chemistry of 4H-3, I-benzoxazines we had occasion to attempt alkylation of 1 by means of potassium amide in liquid ammonia followed by benzyl chloride. There was obtained on workup a solid product clearly different from starting material. The nmr spectrum of this, while not very informative, did show that this product was not the hoped for benzylated material. Elemental analysis and the mass spectrum showed the unknown to be isomeric with starting material. Treatment with acetic anhydride in pyridine gave a derivative whose ir (max 1750 cm-') and nmr (singlet at 2.08 6 ) spectra indicated an 0-acetate. Catalytic reduction of the rearrangement product over pall?dium on charcoal gave 5-chloro-2,3-diphenylindole identical in all respects with an authentic sample (I). These data permit the formulation of the product of the amide reaction as the 3H-indol-3-ol, 2. Though the corresponding 2,3-dialkyl compounds have received considerable attention as products of the air oxidation of indoles (2-6) the diary1 compounds prepared. \ll*-1 . w 5 appear not to have been hitherto Scheme I 2 3 2 \ \ \ I 'sH5, ,,-Formation of the indolol can be rationalized a h in Scheme I. The reaction is initiated by abstraction of the acidic benzhydryl proton, an assumption borne out by the observation of a transient deep color; the resulting carbanion then adds intramolecularly to the electrophilic imino-ether. "Return" of the electron pair with consequent opening of the oxirane leads to the alkoxide of the observed product; this is neutralized in the course of the workup. With this information at hand, we undertook a study of the scope of this novel rearrangement. Preparation of Starting Materials. The requisite 4H-3,I-benzoxazines were readily pre-Scheme I1 0 Ar 4 5 6 l'lir,