Structure, Nomenclature and Properties of Azepines

Session Objectives

By the end of this session, students will be able to:

Discuss the chemistry, reactivity, properties and method of synthesis of Azepines

Azepines

• Seven member heterocyclic ring compounds have received much attention in the past few years owing to its wide range of biological activity.

• Azepines are heterocycles of seven atoms, with a nitrogen replacing a carbon at one position.

A well known azepine is caprolactam

• Skeletal formula of caprolactam. ( Azepan-2-one)

• caprolactam produced goes into the manufacture of Nylon 6.

• Caprolactam is also used in the synthesis of several pharmaceutical drugs including pentylenetetrazol, meptazinol, and laurocapram.

Seven member heterocycles which containing nitrogen

• Benzazepine: bicyclic structure consisting of fused benzene and azepine rings; many compounds with this structure react with biogenicamine receptors, and so are psychotropic and neurotropic.

Examples of benzazepines

Fenoldopam

Structure, nomenclature and properties of diazepine. Benzodiazepine

• Diazepine is a seven member heterocyclic compound with two nitrogen atoms (e.g., in ring positions 1 and 2) and three double bonds.

• When diazepine combined with a benzene ring, these is the basis of the benzodiazepine family . In these compounds the nitrogen atoms are at the 1 and 4 positions as, for example, in clobazam (depending on the position of the fused benzene ring, the nitrogen atoms are also in positions number 1 and 4).

• The benzodiazepines are a class of psychoactive drugs with varying hypnotic, sedative, anxiolytic (anti-anxiety), anticonvulsant, muscle relaxant and amnesic properties, which are mediated by slowing down the central nervous system. Benzodiazepines are useful in treating anxiety, insomnia, agitation, seizures, and muscle spasms, as well as alcohol withdrawal. They can also be used before certain medical procedures such as endoscopies or dental work where tension and anxiety are present, and prior to some unpleasant medical procedures in order to induce sedation and amnesia for the procedure. Benzodiazepines are also used to treat the panic that can be caused by hallucinogen intoxication.

• Benzodiazepines can cause a physical dependence and a benzodiazepine addiction to develop and upon cessation of long term use a benzodiazepine withdrawal syndrome can occur.

Nitrazepam

• Nitrazepam is a nitrobenzodiazepine

• It is a 1,4 benzodiazepine, with the chemical name 7-nitro-5-phenyl-1,3-dihydro-1,4- benzodiazepin-2-one.

• It is a hypnotic drug with sedative and motor impairing properties, anxiolytic, anticonvulsant and skeletal muscle relaxant properties. It is long acting drug, has lipophilic and hepatometabolitic properties via oxidative pathways. It acts on benzodiazepine receptors in the brain which are associated with the GABA receptors (gamma-aminobutyric acid). GABA is a major inhibitor neurotransmitter in the brain, involved in inducing sleepiness, muscular relaxation and control of anxiety and seizures, and slows down the central nervous system.

Diazepam

• (4N-oxide  7-chlorine-1-methyl-5-phenil-1,3-dihydro-2Н-1,4-benzodiazepin-2-оne)

• Diazepam first marketed as Valium by Hoffmann-La Roche, is a benzodiazepine derivative drug. It possesses anxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant and amnestic properties. It is commonly used for treating anxiety, insomnia, seizures, muscle spasms, alcohol withdrawal and benzodiazepine withdrawal.

• Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1:16 in ethyl alcohol, 1:2 in chloroform, 1:39 in ether, and practically insoluble in water.

Qualitative reactions on benzodiazepines

1. With concentrated acids (H2SO4, HCl, HClO4) derivatives of benzodiazepines form color salts.

2. Heterocyclic nitrogen atom gives positive reaction with common alkaloids precipitate reagents.

3. Formation of azodyes after primary hydrolysis:

4. Noozepam by heating with conc. H2SO4 hydrolyzed with formation of formaldehyde, which forms violet color with fuxinsulfite acid.