Theme: Derivatives of barbituric acid: properties, analysis, storage, action and use. Primidone as structural analog of barbiturates.

 

 

 

Derivatives pyrimidine

         In structure of many natural and synthetic drugs is pyrimidine – hexatomic heterocycle with two atoms of Nitrogene which are in position 1,3:

         Completely hydrogenated cycle of pyrimidine names hexahydropyrimidine:

        

In medical practice the synthetic preparations containing in a basis hexahydropyrimidine cycle with three oxogroups =С=О in position 2,4,6 – derivatives of barbituric acid are widely applied:

barbituric acid

And 1,2,3,4-tetrahydropyrimidine cycle with two oxogroups in position 2 and 4 – derivatives of uracil:

    Uracil

         Both groups of preparations play the important role in medicine as sleeping medicines (barbiturates) and for treatment of malignant tumour (derivatives of uracil).

         Derivatives of pyrimidine concern uracil, thymine and cytosine – the pyrimidine bases, which are a part РNA (ribonucleic acid) and DNA, playing the important role in the course of synthesis of protein and transfer of the genetic information.

 

 

 

Drugs – derivatives of barbituric acid

Barbituric acid represents cyclic ureide – a product of condensation of carbamide (urea) with the dibasic malonic acid:

The chemical name of barbituric acid – 2,4,6-trioxohexahydropyrimidine .

Derivatives of barbituric acid are products of condensation of a carbamide with derivatives of malonic acid:

                              

          Carbamide               derivative of malonic acid                     derivatives of barbituric acid

                                          

         As the condensation product contains the closed system with two atoms of the Nitrogene in position (1 and 3), therefore barbiturates consider as derivatives of pyrimidine.

 

Chemical properties barbituric acid and barbiturates

         Barbituric acid and its derivatives have the acid nature. Thus barbituric acid in 5–6 times is stronger acetic acid. 5-Monosubstituted of barbituric acid (for example, 5-ethylbarbituric acid) – enough strong acids, and 5,5-disubstituted of barbituric acid (for example, 5,5-diethylbarbituric acid) – very weak acid.

         Acid properties of these compounds are caused keto-enol tautomerism of  barbituric acid – at the expense of Hydrogene atoms of methylene groups  –СН₂–.

 

 

 

 

 

                                                                         

 

        

Besides, at the expense of Hydrogene atoms of imide groups-NH – it is possible imido-imidolnic tautomerism:

        

 

 

For barbiturates, in which Hydrogene atoms of methylene groups are substituted on radicals, it is possible only imido-imidolnic tautomerism (lactam-lactim tautomerism).

 

 

Thus it is necessary to notice, that unlike barbituric acids its derivatives in water solutions almost not dissociates; at presence of ions ОН^–– they dissociates as acids also are capable to give salts with metals:

 

 

 

 

 

 

 

Barbituric acid and its salts in itself do not show medical properties and consequently are not drugs.

 

 

 

General formula of barbiturates (imide form):

 

 

 

 

 

 

 

General formula of Na-salts (imidol form):

 

 

 

 

 

Table 1

 

 

Chemical structure of preparations – derivatives of barbituric acid

 

Preparation (drug)	Substituent				Formula (name)	Duration of action
	R (1)		R1 (5)	R2 (5)
Barbiturates
Barbital   (Barbitalum, Barbitone, Venoral, Diethyl- barbituric acid)		–	–C2H5	–C2H5	5,5- diethyl- barbituric acid	Long hypnagogue
Phenobarbital (Phenobarbitalum, Luminal)		–	–C2H5	–C6H5	5-ethyl-5-phenyl-barbituric acid or 5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione	Long hypnagogue, antiepileptic agent
Benzonal (Benzonalum)			–C2H5	–C6H5	1-benzoil-5-ethyl-5-phenylbarbituric acid	Not hypnagogue action, antiepileptic agent
Sodium salts of barbiturates
Barbital sodium (Barbitone sodium, Barbitalum-Natrium)	–		–C2H5	–C2H5	sodium 5,5-diethylbarbiturate	Long hypnagogue
Hexenal (Hexenalum)	–CH3		–CH3		1,5-dimethyl-5 (cyclohexene-1¢–yl)-barbiturate sodium or 1,5-dimethyl-5 (tetrahydrobenzene-1¢–yl)-barbiturate sodium	Short-term hypnagogue, narcotic (intravenously narcosis)
Barbamyl (Barbamylum, Sodium amital, Sodium amobarbital)	–		–C2H5		Sodium 5-ethyl-5-isoamyl-barbiturate	Average hypnagogue
Tiopental sodium (Thiopentalum-Natrium)	–		–C2H5		sodium derivative of 5-ethyl-5-[(1RS)-1-methylbutyl]-2-thioxo-2,3-dihydropyrimidine-4,6(1H,5H)-dione or Sodium 5-ethyl-5(2′-amyl)-2-thyobarbiturate	Strong hypnagogue, short-term, narcotic