Spiro hydantoins

Condensation of o-phenylenediamine or xV-methyl-o-phenylcne-diamine with alloxan (8) in neutral solution gives the ureides (9) and (10), respectively However, reaction of o-phenylenediamine with 1,3-dimethylalloxan (13) yields quinoxalin-3-one-2-carboxymethyl-amide (14), rather than the dimethyl ureide. Methylation of (9) in acetone in the presence of potassium carbonate gives the spiro-hydantoin (11). 

Several 3-vinyl- and 1,3-divinyl-hydantoin derivatives have been prepared and converted to polymers having pendant hydantoin groups, e.g. (66) (B-74MI11100). Interesting spiro hydantoin polymers (67) are readily prepared from the very reactive 5-methylenehydantoin, hydrolysis of which cleanly produces polymers containing a-aminoacrylic acid units and having corresponding polyampholytic properties. 

S. Mio, Y. Kumagawa, and S. Sugai, Synthetic studies on (+)-hydantocidin (3) A new synthetic method for construction of the spiro-hydantoin ring at the anomeric position of D-ribofuranose, Tetrahedron 47 2133 (1991). 

Spiro hydantoins, (III) prepared by Webb (4) and hydantoin and thiohydantoin, (IV), derivatives prepared by Poitout (5) were effective as somatostatin receptor agonists and were useful in treating hypersecretion disorders. 

Table 18 5-HTia, 5-HT2a and D2 affinities and 5-HTia/5-HT2a functional activities of spiro-hydantoins...

Spiro hydantoins such as 225-227 (Table 19) were tested for their inhibitory activity against tumor necrosis factor a (TNF-a) converting enzyme (TACE) [82]. The compounds exhibited strong inhibitory activity against porcine TACE and excellent selectivity over MMPs (Table 11). For compound 226, the (55, 6R) enantiomer was more than 80-fold less active against pTACE. Boc or isopropylacetyl pyrrolidine derivatives of 227 were also equipotent with 227. 

Several glycosilidene analogs with spiro-hydantoins and spioro-thiohydan-toins exhibited potent inhibition against GPs. Figure 11 shows some of the examples. 

Spiro-hydantoin Spiro hydroxyacetic acid unit Aldose reductase inhibitor Lipinski et alP... 

Sorbinil 282 is a compound of potential therapeutic interest, because it prevents or alleviates the chronic complications of diabetes mellitus, due to its ability to inhibit the enzyme aldose reductase. Sarges et al. prepared 282 and its enantiomer by the reaction sequence shown in Scheme 12.71, involving a brucine resolution of the racemic hydantoin precursor 284. " The free base of brucine forms a crystalline complex with 282, whereas the other enantiomer of 282 only forms a crystalline complex with brucine hydrochloride. Since this resolution technique does not work with certain congeners of sorbinil, a synthesis via an asymmetric induction sequence (Scheme 12.72) has also been developed that seems generically applicable to optically active spiro hydantoins. Both methodsrequired 2,3-dihydro-6-fluoro-47/-l-benzopyran-4-one 283 and the introduction of the amino acid functionality... 

A. Piperidine-4-spiro-5 -hydantoin (1). A 1000-mL, single-necked, round-bottomed flask equipped with a magnetic stirbar and an addition funnel fitted with an argon inlet is charged with 4-piperidone monohydrate hydrochloride (30.0 g, 195 mmol), ammonium carbonate (41.3 g, 420 mmol), 250 mL of methanol, and 150 mL of deionized water (Note 1). The mixture is allowed to stir at room temperature until all solids dissolve and then a solution of potassium cyanide (26.7 g, 410 mmol) (Note 2) in 100 mL... 

Triturating with chloroform is necessary to successfully remove a trace amount of 1-tert-butyloxycarbonylpiperidine-4-spiro-5 -(r-tert-butyloxycarbonyl)-hydantoin. 

In an attempt to form orally active penicillins unrelated to ampicillin, use was made of the fact that certain spiro a-aminoacids, such as 9, are well absorbed orally and transported like normal amino acids. Reaction of cyclohexanone with ammonium carbonate and KCN under the conditions of the Bucherer-Bergs reaction led to hydantoin 10. On acid hydrolysis, a-amino acid 11 resulted. Treatment with phosgene... 

The Ugi-4CR between cyclic ketones, primary amine hydrochlorides, potassium thiocyanate (or selenocyanate), and 2,2-diethoxyethyl isocyanide [91] afforded the spiro 2-thio-(or seleno)hydantoin-4-imines 166. On heating in acetic acid, compounds 166 underwent carbonyl deprotection and cyclization to spiro imidazo[l,5-ajimidazoles 167 (Scheme 2.60). 

The synthesis of N-(conversion into 3-spiro-5-hydantoin derivatives (31) have been described.15... 

The Bucherer-Bergs hydantoin synthesis has been employed to build spiro compounds 221 as 5-HTlA modulators [81]. The compounds were prepared from... 

Note that the highest IDT was obtained with the cyclopenta-methylenehydantoin resin derived from cyclohexanone. It is tempting to speculate that this inflexible alkylene moiety was ineffective in shielding the hydantoin ring, but subsequent comparison of the hydrophobic-hydrophilic balance of amine-cured resins appeared to rule out this explanation probably the stiff spiro structure contributed to the high Tg, just as it contributed to the high melting point of the resin itself (lie). 

Among many studies which confirm the Edward s rule is that dealing with tropane-3-spiro-5 -hydantoins 34-36 in Scheme 4.49,67... 

A/-Alkylgranatanine-3-spiro-5 -hydantoins obtained by the Bucherer-Bergs methods have the a-configuration.68-71 The stereoselectivity of the Bucherer-Bergs and Read reactions of bicyclo[3.2.1]octan-3-one72 and N-methyl-10-azabicyclo[4.3.1]decan-8-one (homogranatanine) has also been... 

Hydantocidin. Hydantocidin (182), C7H10N2O6, is elaborated by S. hygroscopicus (278). It is unique in that the anomeric carbon of the ribosyl moiety forms the spiro bond of hydantoin (279). The ribofuranose moiety which has been reported to be in a G -endo conformation (279) has been synthesized (280,281). Hydantocidin is a herbicidal nucleoside with activity against monocotyledenous and dicotyledonous plants. 

Lipinski, C.A., Aldinger, C.E., Beyer, T.A., Bordner, J., Burdi, D.F., et al. (1992) Hydantoin isosteres. In vivo active spiro hydroxy acetic aldose reductase inhibitors. J. Med. Chem. 35 2169-2177. 

C1oHi6N2O2, Cyclo-octane-spiro-5 -hydantoin, 45B, 264 Cl0H16N2O2, 7-(Aminoethylidene)-6-methoxy-8-oxo-1-azabicyclo-[4.2.0]octane, 45B, 264... 

C,iH,7N302r N-Methylgranatanine-3-spiro-5 -hydantoin, 44B, 270 CliH,7N3O2, 3-Ethyl-3-azabicyclo[3.2.1]octane-8-spiro-5 -hydantoin, 45B, 310... 

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