Chapter 17. Pyrimidine derivatives

Medicinal substances of this class are derivatives of a heterocyclic compound with two hetero nitrogen atoms - pyrimidine (1,3-diazine):

	Boiling point	124 °С
	Melting point	22.5 °С

A pyrimidine fragment is an integral part of some vital biologically active substances, for example, nucleotides, vitamins of the B1 and B2 groups.

Substances of the pyrimidine class also include many synthetic medicinal substances that are not copies of natural compounds, as barbituric acid derivatives do not occur in nature.

Classification

Most synthetic medicinal substances ― pyrimidine derivatives ― can be classified into the following subgroups:

derivatives of pyrimidine-2,4,6-(1H, 3H, 5H)-trione, or barbituric acid (barbital, phenobarbital, benzobarbital (benzonal), etc.);

derivatives of pyrimidine-4,6-dione (primidone (hexamidine);

derivatives of pyrimidine-2,4-dione, or uracil dioxomethyltetrahydropyrimidine (methyluracil), fluorouracil, tegafur (flutorafur), zidovudine (azidothymidine);

derivatives of pyrimidin-2-one, or cytosine (cytarabine);

cytosine (cytarabine).

Derivatives of pyrimidine-2,4,6-trione

According to the pharmacological effect, barbiturates are divided into the following groups:

• sleeping pills/hypnotic (barbital, sodium barbital);
• injectable anesthetics/non-inhalation general anesthetics (hexobarbital (hexenal), sodium thiopental);
• antiepileptic drugs (benzobarbital (benzonal), phenobarbital).

The structure of these drugs is based on barbituric acid, a condensation product of urea and malonic acid:

In barbituric acid, the hydrogen atoms have higher mobility so this structure has the various tautomer forms. Barbituric acid is a cyclic ureide, for which two types of tautomerism are possible: keto-enolic and lactim-lactam:

Derivatives of barbituric acid represent its 5,5-disubstituted, capable of lactam-lactam tautomerism. This ability determines the presence of two types of drugs in this group:

• in acid form (lactam, slightly soluble in water);
• in salt form (lactic, water-soluble).

DERIVATIVES OF THE LACTAM FORM OF BARBITURIC ACID

Medicinal substances belonging to this subgroup have the general formula

Latin, international non-proprietary, trade name, chemical). Chemical structure	Physicochemical properties.
Barbitalum. Barbital 5,5-diethylbarbituric acid, or 5,5-diethylpyrimidine-2,4,6- (1H, 3H, 5H)-trione. М.м. 184.20 С8H12N2O3	Odorless white crystalline powder, slightly soluble in water, soluble in boiling water and 95% alcohol, freely soluble in solutions of alkalis, slightly soluble in ether and chloroform. Sleeping pill
Phenobarbitalum. Phenobarbital 5-Ethyl-5-phenylbarbituric acid or 5-phenyl-5-ethylpyrimidine-2,4,6-(1H, 3H, 5H)-trione М.м 232.24 С12H12N2O3	White, odorless, crystals, crystalline powder, which may exhibit polymorphism. It is stable in air. Its saturated solution has a pH of about 5. Very slightly soluble in water, freely soluble in alcohol, in ether, and in solutions of fixed alkali hydroxides and carbonates; sparingly soluble in chloroform. Sleeping pill
Benzonalum. Benzobarbital. Benzonal 1-benzoyl-5-ethyl-5-phenylbarbituric acid 1-benzoyl-5-ethyl-5-phenylpyrimidine-2,4,6- (1H, 3H, 5H)-trione M.m. 336.34 С19H16N2O4	White crystalline powder; Slightly and very slightly soluble in water, freely soluble in chloroform, soluble in ether, sparingly soluble in 95% alcohol. Antiepileptic drug

Medicinal substances of the lactim (water-soluble) form of barbiturates correspond to the following general formula:

Latin, international non-proprietary, trade name, chemical). Chemical structure	Physicochemical properties.
Thiopentalumnatrium. Sodium thiopental. A mixture of the sodium salt of 5-ethyl-5- (1-methyl-butyl)-2-thiobarbituric acid with anhydrous sodium carbonate. М.м. 264.32 М.м. 105.99 С11H17N2NaO2S Na2CO3	Thiopental Sodium for Injection: white to off-white, crystalline powder, or yellowish-white to pale greenish-yellow, hygroscopic powder. May have a disagreeable odor. Solutions are alkaline to litmus. Solutions decompose on long term storage, and on boiling precipitation occurs. Anesthetic for intravenous anesthesia
Hexenalum Hexobarbital. Hexenal 1,5-Dimethyl-5-(cyclohexen-1-yl) - sodium barbiturate or 1,5-dimethyl-5-(cyclohexen-1-yl-pyrimidine-2,4,6 - (1H, 3H, 5H)-trione monosodium salt М.м. 258.25 С12H15N2NaO3	White foamy mass. Decomposes in air under the influence of carbon dioxide. Hygroscopic. Very soluble in water and 95% alcohol, practically insoluble in ether and chloroform. Anesthetic for non-inhalation general anesthesia
Barbitalumnatrium. Sodium barbital. Sodium barbital 5,5-diethyl sodium barbiturate or 5,5-diethyl pyrimidine-2,4,6-(1H, 3H, 5H)-trione monosodium salt М.м. 206.18 С8H11N2NaO3	Odorless white crystalline powder. The aqueous solution has an alkaline reaction to phenolphthalein. Very soluble in water, slightly soluble in 95% alcohol, practically insoluble in ether. Sleeping pill