2,5-oxazolidinedione

Oxazolidine-4,5-dione, At-benzoyl-synthesis, 6, 231 Oxazolidinediones reactions, 6, 214 structure, 6, 179 Oxazolidine-2,4-diones as anticonvulsants, 1, 166 NMI 6, 181 reactions, 6, 214 s mthesis, 6, 231 OxazoIidine-2,5-diones crystal structure, 6, 185 reactions, 6, 214 polymers, 1, 307 s mthesis, 6, 231 Oxazolidine-4,5-diones synthesis, 6, 231 Oxazolidines... 

One of the standard methods for construction of the basic heterocyclic ring was elaborated not long after the turn of the century. Thus, condensation of ethyl lactate with guanidine leads to the imine of the desired ring system (47), possibly by a reaction scheme such as that outlined below. Hydrolysis affords the oxazolidinedione (48). Methylation in the presence of base gives 49. 

Therapeutic Function Anticonvulsant Chemical Name 3,5,5-trimethyl-2,4-oxazolidinedione Common Name Troxidone Structural Formula ... 

Administration of trimethadione (Tridione) may result in hematologic changes, such as pancytopenia (decrease in all the cellular components of the blood), leukopenia, aplastic anemia, and thrombocytopenia Also reported are various types of skin rashes, diplopia (double vision), vomiting, changes in blood pressure, CNS depression, photosensitivity, and fatal nephrosis. Because these dm have been associated with serious adverse reactions and fetal malformations, they should be used only when other less toxic dm are not effective in controlling seizures. The oxazolidinediones may precipitate a tonic-clonic seizure... 

OXAZOLIDINEDIONES. The oxazolidinediones are used only when other, less-toxic dm have not been effective in controlling the seizure disorder because they have been associated with fetal abnormalities and serious adverse reactions. 

OXAZOLIDINEDIONES. Drowsiness is the most common adverse reaction and, as with the other anticonvulsants, tends to subside with continued use Visual disturbances may also occur. The patient with a visual disturbance is assisted with ambulation and oriented carefully to the environment. The nurse ensures that the environment is safe The patient may be especially sensitive to bright lights and may want the room light to be kept dim. Because photosensitivity can occur, the nurse must keep the patient out of the sun. The nurse instructs the patient to use sunscreens and protective clothing until the individual effects of the drug are known. 

The oxazolidinedione ring is unstable in aqueous basic solution the N-N bond is also susceptible to cleavage when attacked by hydroxyl radicals Famoxadone is an oxazolidinedione fungicide acknowledged for effective preventive effects and broad fungicidal spectrum. Famoxadone is used to control... 

X-Ray diffraction analyses of vincristine methiodide (39) and vinzoli-dine 1-naphthalene sulfonate (40) provide atomic coordinates of compounds that are either modified in the velbanamine portion (alkylation at N-6, Fig. 3) or in the vindoline portion (a spiro-fused oxazolidinedione at C-3 and C-23, Fig. 4). These structures show a chair-boat conformation for ring C with C-8 exhibiting an endo pucker. Ring D is clearly in a chair conformation, but, in contrast to the conclusions drawn from C-NMR studies, the N-6 -C-7 bond is axial relative to the piperidine ring. 

Unsubstituted oxazolidinediones are prepared directly from the unsubstituted C-3 amides. Treatment of 4-deacetylvinblastine amide (59) with sodium hydride in tetrahydrofuran followed by the addition of dimethyl carbonate gives 4-deacetyl-3-oxazolidinedione (101) in 40% yield. 

Reaction of 1 with excess 103 in toluene gives the mixed carbamate (104) in 21% yield after chromatography on silica gel. Reduction of the S—S bond present in this carbamate is accomplished with zinc dust in acetic acid to give the A(-(2 -mercaptoethyl) oxazolidinedione (105) in high yield. Dimerization of 105 is then achieved by reaction with excess aqueous potassium ferricyanide to give the disulfide (106). 

Oxazolidinedione derivatives of 1 were found to be exceptionally stable to acidic hydrolysis (81). Selective hydrolysis of the C-4 acetate in 96 without affecting the integrity of either the oxazolidinedione ring or any... 

A number of substituted bisindole oxazolidinedione derivatives were prepared using the methods described above (Table VI) (79-81). When examined for their ability to induce a mitotic block in CHO cells, these compounds were active from 2 to 0.002 p.g/ml (Table VII), and compounds having the greatest degree of potency in this in vitro system were evaluated in several experimental tumor systems (Table VIII). The in vitro potency of these compounds appears to correlate with their in vivo potency as reflected by the minimum effective dose that could be administered without toxicity. Several of these compounds were evaluated for their antitumor efficacy when administered by the oral route (Table IX). Compounds 96 and 107 were shown to be exceptionally active in this regard. 

Antitumor Activity of C-3 Oxazolidinedione Derivatives WHEN Administered Orally... 

The importance of the C-3 functionality and its attendant effect on conformation is illustrated by the discovery of the oxazolidinedione vinzoli-dine (107). This group of compounds represents a serendipitous observation of an orally active vinca alkaloid, but unfortunately the clinical application of this compound was not fully realized. 

Oxazolidinediones Trimethadione Absence 0 Demethylated to dimethadione 3% excreted unchanged... 

Activated A-alkyl-O-acylhydroxamic acid derivatives 75 undergo base catalysed rearrangement to give 2-acyloxyamides 76 in good to excellent yields (50-100%) (equation 26). These precursors of 2-hydroxy amides (77) are good intermediates to prepare ethanol-amines, oxindoles and oxazolidinediones. 

As Moody and co-workers (173) discovered, isomtinchnones can occasionally form even when they are not the desired product Thus, these workers inadvertently obtained an oxazolidinedione via an isomtinchnone rather than the desired oxoindo-line when a diazo compound was treated with rhodium(II) perfluorobutyramide in their studies leading ultimately to a synthesis of the marine alkaloid convolutamy-dine C. 

Benkovic and co-workers also isolated spirocyclic 2-amino-4(5/7)-oxazolones during their studies on pterin-dependent amino acid hydroxylases (Scheme 6.24). Reaction of 91 with 0-methyl hydroxylamine or semicarbazide at pH 4.8 yielded 92a and 92b, respectively. The authors showed that 92 does not simply result from reaction of the corresponding oxazolidinedione with either reagent. Further, by using H2 0 as the solvent they demonstrated that there was no incorporation into the product. Two different but precedented mechanisms were proposed to account for this rearrangement. The stereochemistry of 92b was confirmed by single-crystal X-ray. 

In principle then, these saturated imides and derivatives are beyond the scope of this chapter. However, the synthesis and reactions of some 3-unsubstituted derivatives of 179 are included in the interest of completeness. No attempt has been made to provide an exhaustive review of all examples of 2,4-oxazolidinediones. Rather, selected examples from the recent literature that illustrate general synthetic approaches or novel reactions are described. 

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