Barbituric Acid Derivatives Jonans Tusiimire, MPS Pharmacy Dept, FOM, MUST Wed, Sept. 16, 2009 PHC 3102: Barbiturates

Introduction Barbiturates are cyclic ureides which are the derivatives of barbituric acid (2,4,6-trioxohexahydropyrimidine). As such barbituric acid has no CNS depressant activity. But substitution at 5th position by alkyl or aryl groups confers sedative and hypnotic activity. Barbituric acid derivatives or barbiturates are prepared by the condensation of urea (or urea derivative) and substituted malonic acid esters.

General Structure

Classification Long acting barbiturates (t1/2 > 8h) Barbitone, Barbital sodium, Phenobarbital, Mephobarbital Intermediate acting barbiturates (t1/2 4 – 8h) Allobarbital, hexobarbitone, pentohexital sodium Short acting barbiturates (t1/2 < 4h) Secobarbitone, hexobarbitone, Pentobarbitone, cyclobarbitone Ultra short acting barbiturates (I-V GAs) Thiopental sodium, Methohexital sodium

Uses Sedative & hypnotic Anticonvulsant (mephobarbital) Antiepileptic (phenobarbital) General anaesthetic (thiopental, thiamylal)

Chemistry 1 Barbiturates are derivatives of barbituric acid (2,4,6-trioxyhexahydropyrimidine): The above shows keto – enol tautomerism of barbituric acid through carbonyl carbon (C-2).

Chemistry 2 Clinically important hypnotic-sedative barbiturates have substitutions at positions 1, 2 and, especially, 5 of barbituric acid. Barbituric acid may be described as a "cyclic ureide of malonic acid."

Chemistry 3 Keto-enol tautomerization allows formation of water-soluble barbiturate salts:

Chemistry 4 The keto – enol tautomerism in barbituric acid is favoured by the presence of two electronegative amido nitrogens flanking the C-2 carbonyl carbon. The enol (lactim) form is favoured in alkaline solution leading to salt formation. The keto (lactam) form is favoured in acid solution. Therapeutically, disadvantages of barbiturates include tolerance, abuse, dependence, hangover and other prolonged effects.

Synthesis Barbituric acid derivatives or barbiturates are prepared from malonic acid or its esters by condensation with urea (or a urea derivative).

1. Barbituric Acid Synthesis

2. Barbital Synthesis

3. Phenobarbitone Synthesis

4. Butabarbitone Synthesis

5. Methylphenobarbitone

6. Quinobarbitone Sodium (Secobarbital sodium)

Some Chemical Names Barbiturates are named as barbituric acid derivatives, e.g:- Phenobarbitone: 5-ethyl-5-phenylbarbituric acid Amylobarbitone: 5-ethyl-5-isopentylbarbituric acid Pentobarbitone: 5-ethyl-5-(1-methylbutyl)barbituric acid Cyclobarbitone: 5-cyclohex-1`-enyl-5-ethylbarbituric acid Hexobarbitone: 5-cyclohex-1`-enyl-1,5-dimethylbarbituric acid

SARs 1 Barbituric acid itself does not possess any sedative (or hypnotic) activity. The sedative/hypnotic activity is produced when the two active hydrogen atoms at position 5 have been appropriately substituted by alkyl or aryl groups. The total number of carbon atoms present in two groups at position 5 must not be less than 4 or more than 10 for their optimal activity.

SARs 2 Only one of the substituents may be a closed chain for good activity (e.g. hexobarbital, cyclobarbital, phenobarbital). The branched chain isomer exhibits greater activity and shorter duration. The drug having greater branching is more potent (e.g. pentobarbital, amylobarbital). Double bonds—if present in alkyl substituents— produce compounds more susceptible to tissue oxidation. Hence they are short acting (e.g. secobarbital).

SARs 3 Stereoisomers have approximately equal potencies. Aromatic or alicyclic substituted analogs are more potent than the corresponding aliphatic analogues having same number of carbon atoms. Short saturated chains at carbon 5 resists oxidation and hence produce long acting derivatives. Long chains are readily oxidized and thus produce short acting barbituric acid derivatives (e.g. barbital, pentobarbital, secobarbital).

SARs 4 Introduction of halogen atoms to 5 – alkyl substituents increases potency Introduction of polar groups (OH, NH2, COOH, SO3H, CO, RNH) to 5 – alkyl or aryl substituents decreases lipid solubility and therefore potency. Alkylation at 1 or 3 positions enhances onset and reduces duration of action (e.g. hexobarbital).

SARs 5 Replacement of oxygen by sulphur at carbon – 2 (thiobarbiturates) shortens on set and duration of action due to increased lipid solubility (e.g. thiopental). But more sulphur at C-4 & C-6 decreases the activity.

General Aspects 1 Hypnotic activity: side chains at position 5 (especially if one of them is branched). Potency and duration of action: length of side chain at position 5 (so, secobarbital and thiamylal are slightly more potent than pentobarbital and thiopental, respectively). More rapid onset and shorter duration of action: sulfur instead of oxygen atom at position 2 (so thiamylal and thiopental have more rapid onset and shorter duration of action than secobarbital and pentobarbital, respectively).

General Aspects 2 Increased incidence of excitatory side effects: methylation at position 1 (methohexital) Increased potency, rate of onset and short action: increased lipophilicity Stereoisomerism: Though their l-isomers are nearly twice as potent as their d-isomers, barbiturates are marketed as racemic mixtures.

General Aspects 3 Methohexital has two asymmetric carbon atoms, so exists as 4 stereoisomers (alpha,beta-d,l-methohexital). The beta isomers are associated with extensive motor activity, so methohexital is marketed as racemic alpha-d,l-methohexital. Different activities among different stereoisomers (enantiomers or enantiomorphs) are consistent with a site of action at a chiral center of a receptor or enzyme.

Mechanism of Action 1 Barbiturates either have a Gamma amino butyric acid (GABA) – like action or enhance the effect of GABA, an inhibitory transmitter. The effects of barbiturates on synaptic transmission are caused by an alteration of post synaptic sensitivity of the neurons to excitatory and inhibitory transmitters. When GABA receptors are activated, chloride channels are open and chloride ion enters the cell, hyperpolarizes it and produces decreased excitation.

Mechanism of Action 2 Barbiturates bind to picrotoxin site of GABA receptor and decrease chloride ion flux and produce an increased chloride ion concentration. They may interfere with the passage of impulses from centers in hypothalamus to the cortex.

Look up for! Structures and chemical names of Pentobarbitone Hexobarbitone Amylobarbitone Quinalbarbitone Cyclobarbitone calcium Chemical names of all the structures mentioned in this presentation.

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