Chapter 22. Phenothiazine derivatives

Aminazin, propazine, ethacizine, etmozin

All phenothiazine derivatives differ in the nature of the radical in the positions 2 and 10. The classification is based on the structure of the radical in position 10.

1. 10-alkyl derivatives of phenothiazine.
2. 10-acyl derivatives of phenothiazine.

10-alkyl derivatives of phenothiazine

1. Aminazine (Chlorpromazine)

Aminazinum (Chlorpromazinе)

2-chloro-10-(3’-dimethylaminopropyl)-phenothiazine hydrochloride

2. Propazine (Promazin)

Propazinum (Promazinе)

10-(3’-dimethylaminopropyl)-phenothiazine hydrochloride

10-acyl derivatives of phenothiazine

1. Unlike the previous subgroup, obtained in Russia.
2. Used as antiarrhythmic and antianginal drugs.

1. Etmozine (Aethmozinum)

2-carbethoxyamino-10-(3’-morpholylpropionyl)-phenothiazine hydrochloride

2. Ethacizine (Aethacizinum)

2-carbethoxyamino-10-(3’-diethylaminopropionyl)-phenothiazine hydrochloride

Pharmachological effect

1. Drugs of the 1^st group are neuroleptics.
2. Drugs of the 2^nd group are antiarrhythmics and antianginals.

Description: white crystalline substances with a tint (because they are very easily oxidized); odorless, soluble in water (as salts); the reaction of the medium is acidic.

Identification

Melting point, UV and IR spectrum.

1. All substances are salts of mineral acids and nitrogen-containing bases.
2. Proof of basic properties.
3. Very easily oxidized.
4. Hydroxamic reaction.
5. Other reactions.

1. Acid-base properties: Proof of salt:

1) soluble in water;

2) the reaction of the medium is acidic;

3) when alkali, ammonia or sodium carbonate are added, the base of the substance precipitates.

2. Proof of a nitrogen-containing base ― with general alkaloid precipitation reagents. The substance is dissolved in water and the reagent is added:

J₂ /КJ = brown precipitate;

HdJ₂ / KJ = white precipitate;

picric acid = yellow precipitate;

BiJ₃ / KJ = orange precipitate.

3. Redox properties: this is the main property of the drugs in this group. Oxidation processes in vivo & in vitro.

Further hard oxidation:

S-S-dioxide (sulfone) is formed; it’s colorless.

The color depends on the nature of the radical in position 2 and does not depend on the nature of the oxidizing agent. If chlorine is in position 2, the color is pink, crimson.

Oxidants:

1) Br₂ when heated, КBrО₃ in an acidic medium;

2) concentrated H₂SO₄;

3) FeCl₃ + H₂SO₄;

4) Се(SO₄)₂ etc., FPN reagent (FeCl₃ + HClO₄ + HNO₃).

Specificity of the oxidation of acyl derivatives: there is an amide bond (electron acceptor) in position 10, which makes it difficult to donate electrons, ⇒ oxidation reactions are difficult. It’s possible to use: 1) conc. H₂SO₄ or 2) hydrolysis of HCl while heating then + Br₂ or КBrО₃.

4. Hydroxamic reaction:

ETHACISINE and ETMOZIN do not display a urethane fragment in a hydroxamic test, because at the moment of hydrolysis there is no acyl residue:

The hydroxamic test involves the amide bond in position 10.

Assay

1. Substances: acid-base titration in a non-aqueous medium.

2. HPLC.