Oxazolidinedione derivative

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... 

On the other hand, Wyeth-Ayerst chemists ° encountered limitations with this methodology during their syntheses of spirocyclic 2,4-oxazolidinediones derived from isoindole (Scheme 6.55). For example, reaction of 246 with chlorosulfonyl isocyanate followed by cyclization with potassium terf-butoxide afforded poor to modest yields of 247 when R was a substituted benzyl group. Cyclization of 246 using ethyl chloroformate (ECF), triethylamine and 4-(dimethylamino)pyridine (DMAP) in refluxing tetrahydrofuran (THF) gave 247 in only 29% yield when R was methyl and failed completely if R was an isopropyl group. However,... 

More recent studies have confirmed that dual activation of PPARy and PPARo subtypes would be beneficial for treating type-2 diabetes [ 139]. In this connection KRP-297, a TZD derivative has been found to express in vitro as well as in vivo affinity for both the PPARo and PPARy subtypes [152], In light of this, Desai and co-workers have investigated the PPARoj/y dual agonistic activity of a series of TZD and oxazolidinedione derivatives (comp, a. Fig. 22, Table 14) to assess their antidiabetic activity [153,154],... 

Table 14 PPAR-a, Thiazolidinedione and oxazolidinedione derivatives in y and dual (d) binding affinity (comp, a, Fig. 22) [ 155] modeling (CoMFA) ...

Fig. 22 Structures of KRP-297 and thiazolidinedione/oxazolidinedione derivatives associated with PPARa/y dual agonistic activity...

Pemoline acts as a CNS stimulant but with minimal sympathomimetic effects. Pemoline, an oxazolidinedione derivative with possible analeptic and CNS-stimulating properties (37.5 mg p.o. daily), is indicated in the treatment of attention dehcit/hyperactivity disorder (ADHD). 

Momosw Y, Maekawa T, Yamano T, Kawada M, Odaka H, Ikeda H, Sohda T (2002) Novel 5-substituted-2,4-thiazolidinedione and oxazolidinedione derivatives as insulin sensitizers with antidiabetic activity. J Med Ghent 45 1518-1534... 

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. 

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. 

The most versatile syntheses of 3-unsubstituted-2,4-oxazolidinediones involve either cyclization of a-hydroxy esters with urea or cyclization of a-hydroxy amides with a carbonate or phosgene. A third very useful approach is cyclodehydration of 0-carbamoyloxy acetic acids. Normally, this method affords 3-substituted analogues in which the 3-substitutent is derived from an isocyanate. However, examples in which an a-O-carbamoyloxy ester has been prepared via chlorosulfo-nyl isocyanate or an equivalent will also be described in this section. Extensions of these methodologies together with new approaches to 2,4-oxazolidinediones follow. Many of the analogues prepared, particularly as potential antidiabetic agents, employ a-hydroxy esters or a-hydroxy amides as precursors, which provides clear evidence of the versatility and generality of these classical approaches. A selection of recent examples will illustrate this point. 

Imperial Chemical Industries (ICI) chemists " prepared a novel series of spirocyclic 2,4-oxazolidinediones 243 derived from 7-substituted isatins (Scheme 6.54). The key intermediate a-acyloxy amides 242 were readily prepared from 241 in three steps. Base-catalyzed cyclization of 242 then afforded the target compounds that were reported to be potent inhibitors of aldose reductase. Pfizer chemists approached 5-substituted isatin spirocyclic analogues 243 via a-hydroxy esters 244 that were converted to the corresponding a-carbamyloxy esters 245 in good yield using chlorosulfonyl isocyanate. Cyclization of 245 with potassium ferf-butoxide then produced 243 in acceptable yield (Scheme 6.54 Table 6.10, Fig. 6.20). 

Kano and co-workers.Once the 2,4-oxazolidinedione moiety has been incorporated, amide reduction then affords an a-hydroxy lactam, the key N-acyliminium ion precursor. Representative examples of 2,4-oxazolidinediones and the products derived from A -acyliminium ion cyclization are shown in Schemes 6.61-6.63, pp. 110-112. 

Antiseizure heterocyclic ring structure. The X varies as follows hydantoin derivatives, -N- barbiturates, -C-N- oxazolidinediones, -0- succinimides, -C-acetylureas, -NH2 (N connected to C2). Ri, R2/ and R3 vary within each subgroup. 

In this chapter, oxazole and its derivatives are named and numbered as in Chemical Abstracts. Thus compound (6) is called 4,5-dihydrooxazole rather than 2-oxazoline or A2-oxazoline, (7) is 2,5-dihydrooxazole, the betaines (3) are named anhydro-5-hydroxy-oxazolium hydroxides and not oxazolium 5-oxides or oxazolium 5-olates, and the oxo derivatives (4) and (5) are 5(4//)-oxazolone and 5(2//)-oxazolone, respectively, the position of the extra hydrogen atom being indicated in parentheses. The fully saturated compound (8) is oxazolidine its oxo derivatives are named oxazolidinones and oxazolidinediones, e.g. compound (9) is 2-oxazolidinone and (10) is 4,5-oxazolidinedione. A formula such as (11) is not meant to imply that all the substituents are methyl groups it represents a general oxazolidine derivative and is used in place of the cumbersome expression (12 R-R = H, alkyl or aryl). 

The fully saturated oxazolidine (31), its three monooxo derivatives, 2-oxazolidinone (32), 4-oxazolidinone (33) and 5-oxazolidinone (34), and the three oxazolidinediones (35)-(37) complete the list of oxazole structures. Oxazolidinetriones (38) have not been reported. 

Oxazolidine-2,5-diones (276) are the anhydrides of iV-carboxy-a-amino acids. They react with nucleophiles, such as water, alcohols or amines, to give unstable N-carboxy acids, esters or amides which lose carbon dioxide (equation 87). The products (277) are themselves nucleophilic reagents and may react with another molecule of the oxazolidinedione to yield a dipeptide (equation 88). The process may continue, leading to a polypeptide. Chiral oxazolidine-2,5-diones derived from optically active a-amino acids undergo stereospecific polymerization (72C501). 

Irradiation of a benzene solution of 5-phenyl Af-benzoylformyl-A-p-tolylthiocar-bamate 48a (Scheme 23) gave 5-phenyl-5-phenylthio-3-p-tolyloxazolidine-2,4-dione 49a in 61% yield accompanied by oxazolidine-2,4-dione dimer (15%), p-tolyl isocyanate (22%), and diphenyl disulfide [29]. Photolysis of 48a in the solid state gave oxazolidine-2,4-dione 49a in 96% yield. For the N-methyl derivative, 48b, compared to the solution photochemistry in which only 8% of oxazolidinedi-one 49b was obtained with a complex mixture, radical cyclization proceeds selectively to give oxazolidinedione in 75% yield in the solid state. Whereas N-p-tolyl and A-methyl derivatives, 48a and 48b, formed achiral crystals, the N-benzyl derivative 48c crystallized in chiral space group P2. Photolysis of the chiral... 

Oxazoles 1, benzoxazoles 2, oxazolium salts 3, and oxazole A -oxides 4 are fully conjugated compounds (Figure 1). In addition, the two mesoionic structures l,3-oxazolium-5-olates 5 and (l,3-oxazolium-4-olates) 6, commonly known as miinchnones and isomiinchnones, respectively, are also considered to be conjugated rings. There are five systems of hydroxyl-substituted oxazoles and they exist in their oxo forms the 2(3H)-, 2(5H)-, 4(5//)-, 5(2//)-, 5(4//)-oxazolones 7-11. Three forms of dihydrooxazoles are known 2,3-, 2,5-, and 4,5-dihydrooxazoles respectively 12-14. The fully saturated ring is called oxazoline 15. The monooxo derivatives are 2-oxazolidinone 16,4-oxazolidinone 17, and 5-oxazolidinone 18. The three variants of oxazolidinediones are 19-21 and the fully oxidized oxazolidi-netrione is 22. 

The a-hydroxy acid-derived 2,4-oxazolidinediones have been successfully utilized as substrates for asymmetric alkylations with a chiral phase-transfer catalyst (Scheme 40). Using 1 mol% of the N-spiro chiral quaternary ammonium bromide catalyst 153, oxazolidinedinone 152 was alkylated in high yield and enantioselectivity and hydrolyzed in situ to give a-hydroxy amides 154 <2006AGE3839>. 

Oxazolidinediones have been prepared by one-pot condensation of benzyl cyanides, isocyanates, and 2-chloro-2-oxoacetate as shown in Scheme 85. The anion derived from BuLi deprotonation of benzyl cyanide attacks the isocyanate to give intermediates 306, which can undergo condensation and cyclization with ethyl oxalyl chloride to give the 4,5-oxazolidinedione products <2004SL1963>. 

Sodium derivative of 5-ethyl-5-methyl-2, 4-oxazolidinedione is obtained by refluxing urea and ethyl-a-hydroxy-a-methylbutyrate for 24 horns in the presence of sodium methoxide, due to eondensation followed by cyclization. N-methylation is carried out by treatment with dimethyl sulphate. 

Butler TC, The effects of N-methylation in 5,5-disubstituted derivatives of barbituric acid, hydantoin and 2,4-oxazolidinedione, /. Am. Ph. Assoc., 44, 367-370 (1955). NB Ofiier reported values barbital (7.8) metharbital (8.2) phenobarbital (7.3) mephobarbital (7.7) N-norhexobarbital (7.9) hexobarbital (8.3). As file values for barbital and phenobarbital are about 0.2 units less fiian the best values in the literature, the remaining values should be regarded as low by the same amount. 

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