Hydantoins structure

The study of the iV-alkyl derivatives of allantoxaidine was taken up by Biltz who proceeded from its formerly accepted hydantoin structure and obtained its monomethyB and dimethyB derivatives. 

The same authors elucidated the origin of allantoin from hy-droxonic acid on which the original hydantoin structure (5) was based and which was formulated as shown in Scheme 2. 

A hydantoin structure can be built by the reaction of a primary amine with CDI to an isocyanate (Section 8.1), followed by conversion with an amino acid [146]... 

The hydantoin structure contains two amide bonds it is obvious that although the preponderance of the polar form in positions 2 and 3 promotes racemization, charge separation in portions 4 and 5 must have the opposite effect. It is, therefore, of considerable interest to note that, of all the substituted hydantoins tested by Bovamick and Clarke (1938), 3-phenylhydantoins were most easily racemized. The phenyl substituent in position 3 favors the polar structure in the amide linkage (1-2) and the normal structure in (3-4), The positive chaise in portion 1 and the inductive effect of the imcharged carbonyl group (4) together, create the best possible conditions for ionization on the asymmetric center. 

Hydantoinase process, outlined in Fig. 1, includes two hydrolases—hydantoin-hydrolyzing enzyme (hydantoinase) and AT-carbamoyl amino acid-hydrolyzing enzyme (carbamoylase)—and is one of the most efficient and versatile methods for the production of optically active a-amino acids. DL-5-Monosubstituted hydantoins, which are used as common precursors for the chemical synthesis of DL-a-amino acids [1], are the starting material of this enzymatic process. Keto-enol tautomerism is a typical feature of the hydantoin structure. Under neutral conditions, the keto form is dominant in alkaline solution, enolization between the 4 and 5 positions can occur, as has been concluded from the fact that optically pure hydantoins readily racemize. This feature is of practical relevance for the complete conversion of racemic hydantoin derivatives to optically pure L- or D-a-amino acids without any chemical racemization step. A variety of hydantoinase and carbamoylase with different stereospecificity were found. They are D-specific hydantoinase (D-hydantoinase), L-specific hydantoinase (L-hydantoinase), none-specific hydantoinase (DL-hydantoinase), D-specific carbamoylase (D-carbamoylase), and L-specific carbamoylase (L-carbamoylase). With the combination of these enzymes, optically pure amino acids are obtained from DL-5-monosubstituted hydantoins (Fig. 2). The wide substrate range of hydantoinases and carbamoylases also gives generality to the hydantoinase process. 

Hydantoin — see also Imidazolidine-2,4-dione Hydantoin, 3-aryl-5-benzyl-structure, 5, 351... 

The hydantoin moiety has been utilized as a biostere for the peptide linkage, transforming a peptide lead into an orally available drug candidate. Therefore, an Arg-Gly-Asp-Ser tetrapeptide (18) lead structure was modified to a non-peptide RGD mimetic as an orally active fibrinogen receptor antagonist 19. ° ... 

Other patent reports covering PDF inhibitors from structural classes different from those discussed above include hydrazides (43) [118], aryl-substituted pyrrolidines (44) [119], benzimidazoles (45, 46) [120-121], hydantoins (47) [122] and oxo-pyrrolidines (48) [123], A prodrug approach utilising PDF has been published by Pei, and patents have been published by NewBiotics, but in this case the compounds of interest are used as substrates rather than inhibitors (49) [124-126]. 

Sequential pyrrolidine and hydantoin ring-forming reactions via intramolecular [2+3] cycloaddition have been applied to the stereoselective solid-phase synthesis of conformationally constrained tricyclic triazacyclopenta [C]pentalene scaffold 43 < 1999JOC8342>. These novel compounds 43 share the structural complexity characteristic of certain alkaloid natural products, angular triquinanes. The retrosynthetic analysis is shown in Scheme 87. 

The described fluorous-tag strategy has also been applied to the synthesis of biaryl-substituted hydantoins (Scheme 7.81) [94]. 4-Hydroxybenzaldehyde was converted into the corresponding perfluorinated species, which was then subjected to a reductive amination. The resulting amine was treated with an isocyanate to produce the fluorous-tagged urea, which spontaneously cyclized to form the corresponding hydantoin. Finally, the fluorous tag was detached by a Suzuki-type carbon-carbon bond formation to furnish the desired target structure in good yield. 

Kammuller, M.E., and Seinen, W., Structural requirements for hydantoins and 2-thiohy-dantoins to induce lymphoproliferative popliteal lymph node reactions in the mouse. Int. J. Immunopharmacol., 10, 997, 1988. 

Lopez-Rodriguez, M.L., Rosado, M.L., Benhamu, B., Morcillo, M.J., Fernandez, E. and Schaper, K.-J. (1997) Synthesis and structure-activity relationships of a new model of arylpiperazines. 2. Three-dimensional quantitative structure-activity relationships of new hydantoin-phenylpiperazine derivatives with affinity for 5-HTIA and oq receptors. A comparison of CoMFA models. Journal of Medicinal Chemistry, 40, 1648-1656. 

This subsection examines the hydrolytic stability of cyclic structures containing a ureido link. Schematically, ring closure can be achieved by N-alkylation or by /V-acylation of the second N-atom of the ureido moiety. The former results in the formation of, e.g., hydantoins and dihydropyrimidines. The latter ring closure leads to, e.g., barbituric acids. Taken together, cyclic ureides can also be regarded as ring structures that contain an imido function with an adjacent N-atom. We begin our discussion with the five-membered hydantoins, to continue with six-membered structures, namely dihydropyrimidines, barbituric acids, and xanthines. 

The heterocyclic ring of hydantoins, like that of succinimides (see Sect. 4.4.2), is hydrolytically cleaved by dihydropyrimidine aminohydrolase (DHPase, EC 3.5.2.2). Since both hydantoins and succinimides are hydrolyzed by the same enzyme, it is not surprising that structural features, such as absolute configuration, ring-substitution, and TV-substitution, exhibit comparable influence on catalysis. 

Structures 16, 2 (R -R = Me), ° 4, if and 137, are all converted to the corresponding hydantoins by aqueous or methanolic hydrochloric acid, but it is possible to achieve selective hydrolysis. Thus, with aqueous ethanoic acid, 4 yields 148 (64%), whereas methanolic chloroethanoic acid cleaves 115 to 149(86%) the salt 137 gives 150 in aqueous methanol. ° ... 

The cyclization of a-halo carboxylic acid ureides can be complicated with products from different modes of cyclization. For example, bromination of 70 at low pH affords the 2-amino-4(5//)-oxazolone 71 in excellent yield, whereas bromination at pH 5-6 generates a mixture of hydantoins 72 and 73 in poor yield (Scheme 6.19)." Japanese workers" reported that cyclization of a-bromoisovaleryl-urea with 28% aqueous ammonia yields 2-amino-5-isopropyl-4(5H)-oxazolone 74, not 75 or 76. The structure of 74 was established spectroscopically and confirmed by hydrolysis to 77 (Scheme 6.20). 

It is structurally and chemically related to tricyclic antidepressant drug imipramine and pharmacologically it is similar to diphenyl hydantoin sodium. It is effective in grandmal and psychomotor epilepsy and also in the treatment of trigeminal neuralgia (a condition characterized by paroxysms of intense pain of stabbing nature within the area of distribution of trigeminal nerve without sensory loss). 

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. 

Phenytoin is a diphenyl-substituted hydantoin with the structure shown. It has much lower sedative properties than compounds with alkyl substituents at the 5 position. A more soluble prodrug of phenytoin, fosphenytoin, is available for parenteral use this phosphate ester compound is rapidly converted to phenytoin in the plasma. 

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