Hydantoins and Barbiturates

5-(Benzylidene)hydantoiii 60, by treatment with a very large excess of chlorosulfonic acid (16 equivalents) at room temperature (6 hours), gave the / -sulfonyl chloride 61, 87% (Equation 

5-Diphenylhydantoin 62, by boiling with the reagent (12 equivalents) for 4 hours, afforded the disulfonyl chloride 63, 82% (Equation 17).  

Repetition of the experiment under the same conditions, except that at the end of the reaction excess thionyl chloride was added to the mixture which was then left at room temperature for 5 days, gave the same product 63 in a slightly higher yield (88%). The NMR spectrum of the bisdimethylsulfonamide derivative of 63 indicated a w,p-orientation of sulfonation as shown in the structure 63.  

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Plaa, G.L. and Hine, C.H., Hydantoin and barbiturate blood levels observed in epileptics, Arch. Int. Phatm. Then, 128, 375-383, 1960. 

Suzuki, H. Kneller, M. B. Rock, D. A. Jones, J. P. Trager, W. F. Rettie, A. E. Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors. Arch Biochem Biophys. 2004, 429 (1), 1-15. 

With carboxyl-derived functions such as esters and amides, the initial activity of the drug, lost in introducing the carboxyl group, is often regained. Amides, ureides, hydantoins and barbiturates share CNS-depressing properties and are frequently indispensable elements of sedative, tranquillizing and anticonvulsant drugs. Nitriles as substituents are often comparable to chlorine atoms, but sometimes more toxic. 

The three most commonly used classes of anticonvulsants for the initial treatment of GCSE are the benzodiazepines, hydantoins, and barbiturates. Five prospective, randomized smdies have compared these therapies for the treatment of GCSE. The first two studies were a blinded comparison of lorazepam versus diazepam in adults and children. The third study was a randomized comparison of... 

Suzuki et al. investigated 24 hydantoin and barbiturate derivatives with respect to their potency to inhibit CYP2C9 [97]. These compounds showed Ki values between 5 and >1000 yM. A standard CoMFA model with a q QQ value of 0.68 could be established. A CoMFA model derived from a structurally more diverse test set, which contained also 39 compounds from previous studies, showed a cross-validation performance of loo ... 

A mixture of succinimide, isopropenyl stearate, and p-toluenesulfonic acid monohydrate stirred and heated 20 min. at 190° with distillation of the resulting acetone N-stearoylsuccinimide. Y 87%. (J. Org. Ghem. 29, 646). - The highly reactive isopropenyl carboxylates, such as isopropenyl stearate, acylate a wide variety of OH- and NH-compounds, even such resistant ones as ferf-butanol, acetanilide, hydantoins, and barbituric acids (J. Am. Oil Ghemists Soc. 45, 189). E. S. Rothman, S. Serota, and D. Swern, J. Org. Ghem. 29, 646 (1964) J. Am. Oil Ghemists Soc. 45, 189 (1968). 

Fludrocortisone is contraindicated in patients with hypersensitivity to fludrocortisone and those with systemic fungal infections. Fludrocortisone is used cautiously in patients with Addison s disease infection, and during pregnancy (Pregnancy Category C) and lactation. Fludrocortisone decreases the effects of the barbiturates, hydantoins, and rifampin. There is a decrease in serum levels of the salicylates when those agents are administered with fludrocortisone... 

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. 

Drugs that may affect metronidazole include barbiturates and cimetidine. Drugs that may be affected by metronidazole include anticoagulants, disulfiram, ethanol, hydantoins, and lithium. 

The pH, temperature, and ionic strength of the mobile phase also affect the cyclodextrin-solute complexation and retention properties. Many enantioseparations using cyclodextrin-modified systems involve solutes with an aromatic ring substituent or similar cyclic structure at the chiral center. A variety of chiral barbiturates, hydantoins, and related compounds have been resolved by using (3-cyclodextrin and alkylated B-cyclodextrin-modified systems. 

Barbiturates, hydantoins, and imides contain functional groups related to amides but tend to be more reactive. Barbituric acids such as barbital, phenobarbital, amobarbital, and metharbital undergo ring-opening hydrolysis, as shown in Scheme 15.80-81 Decomposition products formed from these drug substances are susceptible to further decomposition reactions such as decarboxylation. The hydrolysis rates of these substances depend on the substituents Ri, R2, and R3. For some allylbarbituric acids, the effects of these substituents on hydrolysis rates can be explained in terms of Hammett s o value.82... 

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. 

I undefined derivatives of barbituric acid, hydantoin and 2,4-oxazolidinedione,... 

Craig this value is from Butler TC, the effects of N-methylation in 5,5-disubstituted derivatives of barbituric acid, hydantoin and 2,4-oxazolidinedione, /. Am. Pharm. Assoc., 44, 367-370 (1955). 

The barbiturate structure resembles that of hydantoins and dialkyl acetyl urea derivatives which are also neuroactive agents (Fig. 4.8). It is clear that the dialkyl substitution at position 5 of barbiturates is essential for their pharmacological activity. Also, if one or two hydrogens are left at position 5 of the barbiturate, the barbiturate will be converted to the trihydroxy pyrimidine derivative, as discussed earlier. 

Acetaminophen may alter blood glucose test results, causing falsely lower blood glucose values. Use with the barbiturates, hydantoins, isoniazid, and rifampin may increase the toxic effects and possibly decrease the therapeutic effects of acetaminophen. The effects of the loop diuretics may be decreased when administered with acetaminophen. Hepatotoxicity has occurred in chronic alcoholics who are taking moderate doses of acetaminophen. 

Phenytoin interacts widi many different drugp. For example isoniazid, chloramphenicol, sulfonamides, benzodiazepines, succinimides, and cimetidine all increase phenytoin blood levels. The barbiturates, rifampin, theophylline, and warfarin decrease phenytoin blood levels. When administering the hydantoins with meperidine, die analgesic effect of meperidine is decreased. 

The ureides hydantoin, parabanic acid, alloxan, barbituric acid, and 4-methyluracil show resonance energies of between 2.3 v.e. and 3.1... 

S2S. Street, H. V., Gas-liquid chromatography of submicrogram amounts of drugs. IV. Identification of barbiturates, hydantoins, amides, imides, carbamates, phenylbutazone, carboxylic acids and hydrazine derivatives by direct derivative fonnation within the gas chromatograph. J. Chromaiogr. 41, 358-366 (1969). 

From the chemical point of view, formally, antiepileptic drugs could be classified as derivatives of hydantoins (phenytoin, mephenytoin, ethotoin), barbiturates (phenobarbital, mephobarbital, and primidone), succinimides (ethosuximide, methosuximide, phensux-imide), benzodiazepines (diazepam, chlorodiazepoxide, clonazepam, lorazepam), oxazo-lidines (trimethadione, paramethadione), and also valproic acid, carbamazepine, and acetazolamide. 

Drugs that may affect estrogens include barbiturates, rifampin, hydantoins, topiramate, and CYP 3A4 inducers and inhibitors. 

Agents that may decrease theophylline levels include aminoglutethimide, barbiturates, charcoal, hydantoins, ketoconazole, rifampin, smoking (cigarettes and marijuana), sulfinpyrazone, sympathomimetics ( -agonists), thioamines, carbamazepine, isoniazid, and loop diuretics. 

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