Barbiturate

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 

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. 

The method of synthesis for thousands of barbital analogs involves the reaction of urea with various derivatives of malonic acid, usually a diethyl ester of a dialkyl-substituted malonic acid. 

The barbiturates are usually administered as the sodium salts. The N-H bonds are acidic and although barbituric acid itself is inactive, a range of activities is obtained that varies with the groups at R and R1. Activity and toxicity both increase with the size of the groups. Branching and unsaturation decrease the duration of action. 

Barbiturates have been used in sleeping pills, but in recent years several other compounds also have been introduced for this purpose. Barbiturates induce a feeling of relaxation, usually followed by sleep, and have been used to provide temporary respite in times of unusual emotional stress, but they will only prolong the stress and patient reliance on the drugs is common. 

The maximum therapeutic index (tolerated dose/minimum effective dose) is highest when the two groups have a total of 6 to 10 carbons. Major drawbacks of their use are their habit formation and their high toxicity when alcohol is present in the bloodstream. 

In general, the barbiturates exert a significant depressant action on the cerebrospinal axis. The relative degrees of depression, sedation, hypnosis or anaesthesia are exelusively dependent on the nature of the barbiturate, its dose and route of administration. 

Barbiturates are cyclic ureides and are formed when a diearboxylic acid reacts with urea. The acids used are generally in the form of ester and are condensed in the presence of sodium ethoxide i.e., C2H5—ONa) e.g., 

Parabanic acid is a cyclic ureide containing a five membered ring, which on hydrolysis by alkali may regenerate the corresponding acid and urea. The cyclic ureides are acidic owing to enolization and hence, they may form metallic salts by replacing the H atom of the -OH group as shown below  

Many cyclic ureides are derived from malonic acid or malonic esters. They are collectively known as barbiturates because of their relationship of malonyl urea or barbituric acid. Barbituric acid is prepared by the following two methods  

The cyclic ureides containing a six membered ring, are also regarded as derivatives of the funda- 

Mechanism of Action. Barbiturates are known to increase the inhibitory effects of GABA (see Chapter 6), and this effect is probably the primary way that these drugs decrease seizure activity. Barbiturates may also produce some of their antiseizure effects by inhibiting calcium entry into excitatory presynaptic nerve terminals and thereby decreasing the release of excitatory neurotransmitters such as glutamate.20 

Adverse Side Effects. Sedation (primary problem), nystagmus, ataxia, folate deficiency, vitamin K deficiency, and skin problems are typical side effects. A paradoxical increase in seizures and an increase in hyperactivity may occur in some children. 

Several members of the benzodiazepine group are effective in treating epilepsy, but most are limited because of problems with sedation and tolerance. Some agents such as diazepam (Valium) and lorazepam (Ativan) are used in the acute treatment of status epilepti-cus (see Treatment of Status Epilepticus ), but only a few are used in the long-term treatment of epilepsy. Clonazepam (Klonopin) is recommended in specific forms of absence seizures (e.g., the Lennox-Gastaut variant) and may also be useful in minor generalized seizures such as akinetic spells and myoclonic jerks. Clorazepate (Tranxene) is another benzodiazepine that is occasionally used as an adjunct in certain partial seizures. 

Chemical Class Barbiturates Amobarbital (Amytal) Mephobarbital (Mebaral) Pentobarbital (Nembutal) Phenobarbital (Solfoton, others) Primidone (Mysoline) Secobarbital (Seconal) Possible Mechanism of Action Potentiate inhibitory effects of GABA may also decrease excitatory effects of glutamate 

Benzodiazepines Clonazepam (Klonopin) Clorazepate (Tranxene) Diazepam (Valium) Lorazepam (Ativan) Potentiate inhibitory effects of GABA 

In addition to various allergic of possibly allergic symptoms produced by barbiturates, barbiturates are metabolized by the cytochrome P 450 hepatic microsomal enzyme system and, by inducing these enzymes, enhance the metabolism of other drugs and presumably promote their immunogenicity. However, no direct evidence in support of this concept is available. 

The barbitmates are the other major group of sedative-hypnotic agents. Similar to the benzodiazepines, they are a group of chemically related drugs and there are many variations in properties, particularly onset of effects and duration of action. The most recognized effects of the barbiturates are centrally mediated and include sedation, hypnosis, decreased anxiety, and, at high doses, anesthetic properties. The mechanism of 

The cyclization step is limited to the formation of rings of seven carbons or fewer. 

PROBLEM 21.9 Cyclopentyl methyl ketone has been prepared from 1,4-dibro-mobutane and ethyl acetoacetate. Outline the steps in this synthesis by writing a series of equations showing starting materials, reagents, and isolated intermediates. 

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

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

Barbituric acid was first prepared in 1864 by Adolf von Baeyer (page 98). A historical account of his work and the later development of barbiturates as sedative-hypnotics appeared in the October 1951 issue of the 7ouma/ of Chemical Education (pp. 524-526). 

In order to detect barbituric acids in organs or body fluids, they must first be concentrated and purified in procedures preceding TLC separation. Processing can be as follows  

The material to be examined is extracted with ethanol on the water bath after evaporating off the ethanol, the residue is taken up in water, the solution acidified with tartaric acid and the barbituric acids extracted with ether. Any strongly acid contaminants which are extracted at the same time may be separated from the barbituric acids by shaking the ether solution with a buffer of pH 4.4. 

The pre-purification of barbiturates to be isolated from urine can likewise be carried out by acid ether extraction [43, 56, 166]. Methylene dichloride has been employed also [34]. Acidification with hydrochloric acid is preferable since, if this is performed with weaker, organic acids, amphoteric medicinal components like sulphonamides, are extracted at the same time [166]. After drying the organic phase with sodium sulphate, further purification on a charcoal or alumina column can be carried out [43, 166]. Urine colouring materials can be removed by shaking the ethereal solution with 5% lead acetate solution [56]. After purification, the 

Blood and tissue are brought to pH 5 with hydrochloric acid and the barbituric acids and their metabolites extracted with methylene dichloride [34] prior homogenisation of tissue is carried out with isotonic potassium chloride solution. Barbituric acids can be isolated from serum by adding 0.1 ml concentrated hydrochloric acid and 2 g anhydrous sodium sulphate to 3 ml serum and extracting the mixture with 15 ml chloroform. 10 ml of this extract are evaporated down, the residue dissolved in 0.2 ml 70% ethanol and an aliquot applied to the thin layer [93]. 

In contrast to these purely acid processing procedures. Sunshine [160] has extracted the barbiturates from stomach fluid and urine under alkaline conditions the solutions were filtered and acidified and the barbituric acids obtained by shaking with chloroform. 

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C. Has hypnotic properties similar to barbitone but its action is less prolonged. For manufacture, see barbiturates. 

White crystals, m.p. 191°C. A barbituric acid derivative. The sodium salt is administered orally as a sedative. 

CaH,3N02. White flaky or crystalline powder, m.p. 126-128°C. Used in (he treatment of barbiturate poisoning, by intravenous injection. 

It is the parent substance of a group of compounds which includes cytosine, thymine and uracil, which are constituents of nucleic acids and barbituric acid and its derivatives, which are important medicinally. 

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. 

Uramll (aminobarbituric acid) (III) may be prepared by the oxidation of barbituric acid (I) to nitrobarbiturlc acid (II), followed by reduction of the latter ... 

Ethyl malonate condenses with urea in the presence of sodium ethoxide to yield barbituric acid (malonylurea) ... 

Supplement 1936 3458-3793 Picrolonic acid, 51. Hydantoin, 242. Uracil, 312. Indigo, 416. Barbituric j acid, 467. Alloxan, 500. ... 

Urea derivadves are of general interest in medicinal chemistry. They may be obtained cither from urea itself (barbiturates, sec p. 306) or from amines and isocyanates. The latter are usually prepared from amines and phosgene under evolution of hydrogen chloride. Alkyl isocyanates are highly reactive in nucleophilic addidon reactions. Even amides, e.g. sulfonamides, are nucleophilic enough to produce urea derivatives. 

The nucleophilicity of the nitrogen atom survives in many different functional groups, although its basicity may be lost. Reactions of non-basic, but nucleophilic urea nitrogens provide, for example, an easy entry to sleeping-pills (barbiturates) as well as to stimulants (caffeine). The nitrogen atoms of imidazoles and indole anions are also nucleophilic and the NH protons can be easily substituted. 

These compounds are prepared m a manner analogous to that of barbituric acid itself Diethyl malonate is alkylated twice then treated with urea... 

Barbituric acids as their name implies are weakly acidic and are converted to then-sodium salts (sodium barbiturates) m aqueous sodium hydroxide Sometimes the drug is dispensed m its neutral form sometimes the sodium salt is used The salt is designated by appending the word sodium to the name of the barbituric acid—pentobarbital sodium for example... 

The various barbiturates differ m the time required for the onset of sleep and m the duration of their effects All the barbiturates must be used only m strict accordance with instructions to avoid potentially lethal overdoses Drug dependence m some mdi viduals IS also a problem... 

Section 21 8 Alkylation of diethyl malonate followed by reaction with urea gives derivatives of barbituric acid called barbiturates, which are useful sleep promoting drugs... 

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