Barbituric acid, derivatives, hypnotics

Cyclic thioureas such as 2-thiouracil 1118 (R = H), its 6-methyl 1118 (R = Me) and 6-propyl derivatives 1118 (R = Pr), as well as thiobarbital 1119 are effective agents against hyperthyroidism, while thiamylal 1120 is used as an anesthetic. A large number of barbituric acid derivatives have hypnotic or sedative effects, and allobarbital 1121 (R = R = allyl), aprobarbital 1121 (R = allyl, R = r-Pr), cyclobarbital 1121 (R = Et, R = 1-cyclohexenyl), pentobarbital 1121 (R = Et, R = 2-pentyl), phenobarbital 1121 (R = Et, R = Ph), propallyonal 1121 (R = isopropyl, R = 2-bromoallyl), and secobarbital 1121 (R = allyl, R = 2-pentyl) are all examples of N-unsubstituted barbiturates, while hexobarbital 1122 represents an N-methylated derivative. 

The utility of barbituric acid derivatives as sedative-hypnotic agents is discussed in more detail later in this chapter. Studies on the chemical simplification of these pyrimidinetrione derivatives led to the discovery that pyridinediones, or glutarimides,... 

Synthetic derivatives (e.g. veronal) of barbituric acid are hypnotics. 

Amobarbital is a barbituric acid derivative of intermediate duration of action. It is administered orally in doses of 15 to 200 mg as a sedative hypnotic and in ampoules of 65 to 500 mg for intravenous and intramuscular injection for the seizure control.6 Following a single oral dose of 120 mg, peak serum concentrations averaged 1.8 mg/L after 2 h.7 After an oral dose of 600 mg distributed over a 3-h period, the peak blood concentration was achieved after 30 min, averaging 8.7 mg/L, with a decline to 4.1 mg/L by 18 h.6... 

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]

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. 

The barbituric acid derivatives, which have been known as hypnotic sedatives [136], were chosen as the first of the heterocycHc 1,3-dicarbonyl compounds for study because they consist of a cyclic diamide structure. The reaction of barbituric acid with 1,1-diphenylethene was conducted in acetic acid at room temperature in air using a catalytic amount of manganese(III) acetate. Surprisingly, solid products were easily obtained as a diastere-omixture, meso and racemic. Although the diastereomers could not be... 

Barbituric acid is the parent of a group of compounds known as barbiturates The bar biturates are classified as sedative-hypnotic agents meaning that they decrease the responsiveness of the central nervous system and promote sleep Thousands of deriva lives of the parent ring system of barbituric acid have been tested for sedative-hypnotic activity the most useful are the 5 5 disubstituted derivatives... 

By far, the biggest class of hypnotic drugs are derivatives of barbituric acid. The action of barbiturates is reliable and reprodueible, they are easy to administer and offer a wide range of activity. 

BARBITURATES. Barbiturates are 5,5 -disubstituted derivatives of barbituric acid (malonyl urea). Barbituric acid does not have hypnotic properties, but its derivatives do, and are widely used in medicine as hypnotic-sedatives. Because of their widespread use, the intentional and unintentional abuse of these drugs is most frequent, and most larger hospitals and medical centers have clinical screening and analytical procedures established to determine such compounds in the body fluids of patients. 

Barbiturates are sedative drugs that are derived from barbituric acid and have the ability to depress the central nervous system and act especially on the sleep center in the brain, thus their sedative and sometimes hypnotic effects. 

In large doses, injected intravenously, it would bum and hurt horribly, because it s a salt and because it instantly throws off the chemical balance of the blood with which it comes into contact. It makes all muscles lock up in extreme contraction that would hurt unbearably. It wouldn t get to all muscles when a prisoner is being killed with it, however. Since the heart is a muscle and it pumps the blood -- the minute that massive dose of potassium salt hits the heart, one would be history and that would be as far as it would travel. "In lethal injection, three chemicals are used to kill. First, sodium pentothal (its trade name) or thiopental sodium (its chemical name). Then one minute later they inject pavulon. One minute later the potassium chloride. Pentothal is a short acting barbituric acid (barbiturate used in anaesthesia) and is commonly called "truth serum" as it s used in narcoanalysis. It knocks one out. It s a hypnotic. Pavulon is a curare derivative which locks up the lungs so one can t breathe. 

Barbiturates are central nervous system depressants used as hypnotic drugs and anesthetics. They are all derivatives of barbituric acid (R=R =H), which has no sedative properties. It is called an acid because the carbonyl groups render the imide hydrogens acidic ... 

Barbituric acid was first synthesized in 1864 by Adolph von Baeyer. It apparently was named at a tavern on St. Barbara s day and is derived from urea. At the turn of the century the great chemist Emil Fischer synthesized the first hypnotic (sleep-inducing) barbiturate, the 5,5-diethyl derivative, at the direction of von Mering. Von Mering, who made the seminal discovery that removal of the pancreas causes diabetes, named the new derivative of barbituric acid Veronal because he regarded Verona as the most restful city on earth. 

The pharmacological activity of barbiturates is also influenced by their acidity, which is attributed to the lactam-lactim tautomer-ism that can occur in all derivatives in which at least one of the ring nitrogens is unsubstituted keto-enol tautomerism also takes place in 5-unsubstituted or mono-substituted compounds (Equation 5.17). Barbiturates must have acidity within certain limits to possess hypnotic activity (156). For example, barbituric acid (Ri, R2, R3, R4 = H), which has a pifa of 4.1 and is >99% dissociated at physiological pH, and the neutral N, iV -disubstituted compound (Ri, R2, R3 = Et, R4 = Ph) that is completely undissociated, are devoid of hypnotic... 

Barbiturates are cyclic imides used as hypnotics and (in the case of pheno-barbital) as anticonvulsants. They are all derivatives of barbituric acid (which is not pharmacologically active) and differ only in their substituents on the 5-position of the ring. Barbiturates contain nitrogen atoms, but the lone pair on the nitrogen is not available for reaction with protons, so barbiturates are not basic. Instead, they behave as weak acids in solution (diprotic actually, though the second ionisation is very weak) the negative... 

The barbiturates are substituted pyrimidine derivatives with an ureide configuration (Fig. 20.4). They are lipophilic weak acids (pKa 7-8) that are weii distributed into brain (see Appendix A for the respective pKa values). Although many barbiturates dispiay sedative-hypnotic activity (see Chapter 19), oniy a few have antiseizure properties. Paradoxically, many barbiturates cause convulsions at larger doses. The barbiturates clinically useful as AEDs are phenobarbital, mephobarbital, and primidone (Fig. 20.8). In laboratory animals, phenobarbital is effective by several tests in nontoxic doses. It is active against electrically induced seizures (MES), and it elevates the threshold for pentylenetetrazole stimulation. The mechanism of antiseizure action for the barbiturates... 

Barbiturates are derivatives of barbituric acid. These substances were once used extensively in clinical practices as sedatives-hynotics. Because of their abuse and physical dependence, their therapeutic application has diminished considerably. The sedative effects of barbiturates are similar to those of alcohol. Higher dosage can cause hypnosis and anesthesia. An intake of barbiturates 10-15 times that of the hypnotic dose can be toxic. Coma and death can result from overdose. 

This test identifies the substance to be examined as a non-nitrogen substituted barbiturate or thiobarbiturate. Barbiturates are a large group of structurally related compoxmds with anxiolytic and hypnotic effect. They are derivatives of barbituric acid (Figure 3.10.1) or thiobarbituric acid (Figure 3.10.2). 

Many derivatives of barbituric acid with certain substituents at C-5, which are made by using C-substituted malonates, are very useful as hypnotics. The most famous is phenobarbital (4.24), whieh has been used clinically for many years. This compound can be made from diethyl ethylphenylmalonate (Scheme 4.23). 

Diesters also react smoothly with the urea derivatives, which undergo displacement of the alkoxy groups to create amide bonds. Barbituric acid can be made this way by reaction of diethyl malonate (9.122, R=R =H) with urea (Scheme 9.64). An important family of pharmaceutical agents results from the use of substituted malonic esters. Thus, with a phenyl and an ethyl substituent the important hypnotic agent, phenobarbital (9.123) is produced. Veronal, which is another important hypnotic, is prepared from diethyl-substituted malonates. 

The term barbiturate is by long usage considered synonymous with hypnotic agents . However, the salts of barbituric acid, and of many of its derivatives, have no observable hypnotic properties in most systems. A consideration of the non-hypnotic barbiturates is one of the main objectives of this section. For comparison, a short review of the structural requirements... 

A very profitable engagement of Fischer was the work on derivatives of malonic and barbituric esters. In 1902 the Professor of medicine, J. von Mering, whom Fischer had met in Strassburg, and who was working in Halle/Saale, visited Fischer in Berlin. He showed him a crystalline substance he had synthesized by the reaction of phosphorous oxichloride, urea and diethylmalonic acid. It seemed to be the diethyl ester of barbituric acid and he asked Fischer to confirm the constitution of this substance. Fischer found that the structure was different. With his nephew Alfred Dilthey he found two ways to obtain it. Mering tested diethylbarbituric acid and found that it was a very active soporific substance. Fischer himself used it successfully. Other derivatives of barbituric acid also showed hypnotic properties. Fischer and Mering published their results in January 1903.2 ... 

The barbiturates, which include several important drugs used as sedatives (tranquilizers) and hypnotics (sleep-producers), are closely related to the pyrimidines. The structural formulas of barbituric acid and two of its derivatives are given below in these formulas the distribution of the hydrogen atoms between oxygen and nitrogen is uncertain, and... 

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