5- -substituted-barbituric acids

Substituted hydurilic acids can be obtained from 5-substituted barbituric acids as shown in Scheme 124 [159]. 

During treatment with LiAlH4, 5-substituted barbituric acids formed 2-oxohexahydropyrimidine derivatives.288 N-Methylated barbiturates (109 R = Ph, 1-cyciohexenyl R = Me, Et) were reduced with LiAlH4, giving 110, while such reduction in the presence of A1C13 led to 111.289 It was sug-... 

The parent compound in this class is barbituric acid (2,4,6(l//,3y/,5//)-pyriniidinetrione). In contrast to its 5-substituted derivatives, it has no hypnotic activity. The first hypnotic barbiturate was 5,5-diethylbarbituric acid (barbital). 5-Ethyl-5-phenylbarbituric acid (phenobarbital) is a long-acting CNS depressant. A large number of 5-substituted barbituric acid derivatives has been prepared. Several of the active compounds have been or are used in medicine [Pg.223]

Anti-inflammatory agents—Al number of l,3-diphenyl-5-substituted barbituric acid derivatives (XXXIX) have been prepared for evaluation as antiinflammatory agents [188-190] since their structures are closely analogous... 

Problem 16.55 Barbiturates are sedative-hypnotic varieties of 5,5-dialkyl substituted barbituric acids. Write the reaction for the formation of Veronal (5,5-diethylbarbituric acid) from the condensation of urea with diethylmalonic ester. [See Problem 17.13(a)]. ... 

Condensation of formyl-pyrroles and -indoles with a wide range of other activated methylene compounds has been reported. These include, for example, hydantoin, which provides a useful synthetic route to tryptophane and j8- (pyrrolyl)alanines, thiohydantoin, rhodanine and AT-substituted barbituric acids (B-77MI30505, 79HC(25-3)357). Flash pyrolysis of the condensation product derived from 3-formyl-2,5-dimethylpyrrole with Meldrum s acid produces 6-hydroxy-2-methylindole, (440) — (441) (74AJC2605), whilst the analogous... 

Chen G, Ensor CR, Bohner B (1966) The neuropharmacology of 2-(o-chlorophenyl)-2-methylaminocyclohexanone hydrochloride. J Pharm Exp Ther 152 332-339 Child KJ, Currie JP, Davis B et al. (1971) The pharmacological properties in animals of CT1341 - a new steroid anaesthetic agent. Br J Anaesth 43 2-24 Christensen HD, Lee IS (1973) Anesthetic potency and acute toxicity of optically active di-substituted barbituric acids. Toxicol Appl Pharmacol 26 495-503 Domenjoz R (1959) Anaesthesist 8 16... 

Fig. 3. Dissociation of Cs-substituted barbituric acids. A, undissociated free acid B, mono-anion C, di-anion.

Clas, S. D., Dalton, C. R. and Hancock, B. C. (1999). Differential scanning calorimetry application in drug development. Pharm. Sci. Technol. Today, 2,311-20. [250] Cleverly, B. and Williams, P. P. (1959). Polymorphism in substituted barbituric acid. 

A relationship between the lipophilicity of the solubilisate, expressed by the partition coefficient between octanol and water, Poctanoi (see Chapter 5), and its extent of solubilisation has been noted for the soluhilisation of substituted barbituric acids by polyoxyethylene stearates, of substituted benzoic acids by polysorbate 20, and of several steroids by polyoxyethylene nonionic surfactants. An exhaustive survey of data for the solubilisation of some 64 dmgs by bile salt micelles revealed linear relationships between log (partition coefficient between micelles and water) and log Poctanoi ach of seven bile salts... 

The formation of some 5-alkyl or 5-arylmethylbarbituric acids has been studied by Sekiya et a/.236-238 The barbituric acid derivatives 65 (o-, m-, p-substituted phenyl, benzyl, styrenyl R1, R2 = H and/or methyl) containing a methylidene bond at the 5-position can be reduced by triethylammonium formate (TEAF) in high yield [Eq. (3)]. Similarly, 5-arylaminomethylene- and 5-alkylaminomethylene-substituted barbituric acids can be converted to 5-methylbarbituric acids.238... 

Unsubstituted, 1-mono- or 1,3-dialkyl- and/or phenyl-substituted barbituric acids (68) can be converted to 5-formimidoyl derivatives by a reaction with s-triazine241 [Eq. (4)]. 

Comparison was made of the free acids, the sodium salts, and mixtures of free acid with anhydrous potassium carbonate. The pyrolysis products of 27 substituted barbituric acids were studied using a Pye argon gas chromatograph. While this technique may have its uses when only a... 

N3. Nelson, D. F., and Kirk, P. L., Identification of substituted barbituric acids by gas chromatography of their pyrolysis products. Anal. Chem. 34, 899-903 (1962). 

As the number of carbon atoms at the fifth carbon position increases, the lipophilic character of the substituted barbituric acids also increases (44). Branching, unsaturation, replacement of alicyclic or aromatic substituents for alkyl substituents, and introduction of halogen into the alkyl substituents all increase the lipid solubility of the barbituric acid derivatives. A limit is reached, however, because as the lipophilic character increases, the hydrophilic character decreases. Although lipophilic character determines the ability of compounds to cross the blood-brain barrier, hydrophilic character also is important, because it determines solubility in biological fluids and ensures that the compound reaches the blood-brain barrier. Introduction of polar groups into the alkyl substituent decreases lipid solubility below desirable levels. Modifications at this position by variation of the alkyl substituents were of primary importance in the development of barbiturates with short (3-4 hours) to intermediate (6-8 hours) duration of action. These barbiturates were once extensively used as sedatives and hypnotics. 

M. Krahl, The effect of variation in ionic strength and temperature on the apparent dissociation constants of thirty substituted barbituric acids, /. Phys. Chem., 1940,44,449 63. 

Krahl ME, The effect of variation in ionic strengfii and temperature on the apparent dissociation constants of thirty substituted barbituric acids, /. Phys. Chem., 44,449-463 (1940). NB Not reliable, not in agreement wifii several others (7.98 0.02). The work of Krahl used careful potentiometric measurements, but was flawed by attempting to correct tor ionic strengths that were too high for the version of the Debye-Hbickel equation used. 

Several authors have noted a relationship between the lipophilicity of the solubilizate, expressed as its partition coefficient between octanol and water, Pocianob its Saturation distribution between micelles and the aqueous phase. Rank-order correlations between the amount of substituted barbituric acid solubilized by polyoxyethylene stearates and their Poctanoi values have been reported by Ismail et al. [133]. Similarly the partition coefficients of several steroids between water and micelles of long-chain polyoxyethylene non-ionic surfactants have been correlated with their ether/water partition coefficients [145], Fig. 5.18 shows a linear relationship between the partition coefficient of a... 

Barbituric acid and 2-thiobarbituric acid are readily prepared by the condensation of diethylmalonate with urea and thiourea respectively, in the presence of sodium ethoxide. The use of substituted derivatives of urea and thiourea and of diethyl malonate will clearly lead to a wide range of barbituric and thiobarbituric acids having substituents in the i, 3, or 5 positions. 

Diethyl malonate has uses other than m the synthesis of carboxylic acids One particu larly valuable application lies m the preparation of barbituric acid by nucleophilic acyl substitution with urea... 

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