Barbiturates structure

Barbiturates. Structural features of barbiturates that are required for hypnotic activity include the following ... 

Properties of the compounds illustrated in Figure 8.11. These pharmacokinetic effects occur in addition to the functional effects of modifications in barbiturate structure. In particular, substitutions at positions Rj and R2 produce agents with increased hypnotic potency and anticonvulsant activity. 

There are a number of compounds which do not essentially possess the malonyl urea or barbiturate structure but exhibit marked and pronounced hypnotic-sedative activity veiy similar to that of the barbiturates. Like barbiturates these are habit-forming to varying degrees. They may be grouped together on the basis of their basic structures, namely ... 

Barbiturates structure-activity relationships 60 Metabolism of barbiturates 60... 

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. 

The structure of barbituric acid was the subject of disagreement for many years, but since 195 2 (52BSB44) the trioxo formulation (57 R = H) has been accepted generally, along with the fact that barbituric acid loses a proton, first from carbon (anion) and subsequently from nitrogen (dianion). Barbital (5,5-diethylbarbituric acid) adopts a similar trioxo form (57 R = Et) (69AX(B)1978). 

Barbituric acid — see also Pyrimidine-2,4,6-trione, perhydro-acidic pK, 3, 60 bromination, 3, 70 fluorination, 3, 70 structure, 3, 68 tautomerism, 2, 27 in thermography, 1, 392 Barbituric acid, iV-alkyl-chlorination, 3, 70 Barbituric acid, 5-aminomethylene-synthesis, 3, 524 Barbituric acid, 5-arylidene-pyridopyrimidines from, 3, 227 Barbituric acid, 1,3-dicyclohexyl-synthesis, 3, 113 Barbituric acid, 2-thio-sensitizing dye... 

Early investigators adduced various kinds of chemical evidence in support of a monohydroxy-dioxo structure for barbituric acid (112) (a) reaction with diazomethane afforded a mono-O-methyl deriva- iye,i59,i6o barbituric acid and its 5-alkyl derivatives are much stronger acids than the 5,5-dialkyl derivatives, and (c) the 5-bromo and 5,5-dibromo derivatives have different chemical properties. - The early physical evidence also appeared to substantiate the monoenol structure, this formulation having been suggested for barbituric acid in 1926 on the basis of its ultraviolet spectrum and again in 1934, In the 1940 s, ultraviolet spectroscopic studies led to the suggestion of other monohydroxy and dihydroxy structures for barbituric acid, whereas its monoanion was assigned structure 113 (a clear distinction between ionization and tautomerism was not made in these papers). 

Each era of medicinal chemistry has been marked by intensive concentration on some structural type in a large number of laboratories. One need only look back in this book to the tables of sulfonamides, barbiturates, and thiazide diuretics, noting the small time span covered by the references to each list. The benzodiazepines have provided such a focus for the past decade. 

Barbituric acid can be considered as a cyclized malonic acid diamide (malonyl-urea). It is therefore a cyclic diketone that may be classified, in the sense of the compounds discussed in Section 12.6, as a coupling component with a methylene group activated by two carbonyl groups in the a- and a -positions. The reaction with arenediazonium salts was studied by Nesynov and Besprozvannaya (1971). These authors obtained coupling products (in good yield) that they considered to be arylhydrazones. Coupling with 4-(phenylazo)benzenediazonium chloride was studied by Chandra and Thosh (1991). The lH NMR spectra of these compounds are consistent with the arylhydrazone structure 12.68. 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Blakey GE, Nestorov lA, Arundel PA, Aarons LJ, Rowland M. Quantitative structure-pharmacokinetics relationships I. Development of a whole-body physiologically based model to characterize changes in pharmacokinetics across a homologous series of barbiturates in the rat. J Pharmacokinet Biopharm 1997 Jun 25(3) 277-312. Erratum in J Pharmacokinet Biopharm 1998 Feb 26(l) 131. 

Another class of molecules which are easily bound to hosts by hydrogen bonds are nucleic bases and related molecules like barbiturates (Hamilton and Little, 1990 Chang et al., 1991). The receptor arrays to bind such molecules often contain 2-acylaminopyridine units or related structures such... 

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative allosteric modulator) and flumazenil (benzodiazepine site antagonist)...

Convulsive disorders are still a serious therapeutic problem and new agents are being actively sought. Classical therapy was based upon the barbiturates that are no longer in favor because of their many side effects and their suicide potential. Interestingly, a seemingly minor structural variation of phenobarbital (152, shown as its sodium salt) leads to an anticonvulsant of increased potency and which has less hypnotic activity. In this case, sodium phenobarbital serves as its own base (so the yield is limited to 50%) and reacts readily with... 

Toon, S., Rowland, M., Structure-pharmacokinetic relationships among the barbiturates in the rat, J. Pharmacol. Exp. Ther. 1983, 225, 752-763. 

An experimental study of barbituric acid found one new polymorph where molecules in the asymmetric unit adopted two different conformations [10]. The conformational aspect was investigated through the use of ab initio calculations, which permitted the deduction that the new form found would have a lower lattice energy than would the known form. It was also found that many hypothetical structures characterized by a variety of hydrogen-bonding structures were possible, and so the combined theoretical and experimental studies indicated that a search for additional polymorphs might yield new crystal structures. 

Transamination of barbiturate derivatives with semicarbazide Hydrolysis and acyl migration of corticosteroid esters Rate enhancement by CTABr depends on substrate structure Substrate micellization inhibits hydrolysis and acyl migration Reddy and Katiyar, 1981 Anderson el ai, 1983... 

These dyes are invariably monoazo compounds with the reactive system attached to the diazo component, owing to the ready availability of monosulphonated phenylenediamine intermediates. Pyrazolone couplers are most commonly used, as in structure 7.82 (where Z is the reactive grouping), and this is particularly the case for greenish yellow vinylsulphone dyes. Catalytic wet fading by phthalocyanine or triphenodioxazine blues is a characteristic weakness of azopyrazolone yellows (section 3.3.4). Pyridones (7.83), barbituric acid (7.84) and acetoacetarylide (7.85 Ar = aryl) coupling components are also represented in this sector, with the same type of diazo component to carry the reactive function. 

Aminoanthraquinone is diazotized advantageously with nitrosylsulfuric acid after being dissolved in sulfuric acid. Coupling the diazo compound onto barbituric acid, for instance, affords a yellow pigment [3] with the structure 79 ... 

Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nudeic add constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH]... 

Acylated derivatives of urea are referred to as ureides. Acylation of urea with a monoacid produces acyclic ureides, whereas diacylation with malonic acid (a diacid) yields the cyclic structure of barbiturates. The acyclic ureides carbromal and bromisoval, now outdated hypnotics, can be considered ring-opened analogues of the barbiturates to be examined in the next subsection. 

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. 

Noncovalent interactions in metal complexes of biomolecules may play an important role in the creation of supramolecular structures around the metal center. For instance, extensive three-dimensional hydrogen-bonded stmcmres grow around metal complexes of barbiturates, recognized as the most widely used drugs for the treatment of epilepsy.Electrostatic interactions between a cation and the Trring of an aromatic molecule (cation-tt interactions) are common motifs in protein structures. Little is known about alkali and alkali-earth cation-tt inter-... 

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