Phenothiazine

Phenothiazines as a subset of the thiazines is known, in which the central, nitrogen - and sulfur -containing thiazine ring carries two fused benzene rings. Many are used as drugs, dyes, and insecticides. The medicinally active phenothiazines possess chemical structure similarities with the first ever discovered neuroleptic - the chlorpromazine. All phenothiazines possess a spatially nearly planar three-ring system, which will be precise on its own ( without substituents ) the name of phenothiazine ( CAS Number 92-84-2, Molecular Formula C12H9NS, an almost insoluble in water, melting at 182-187 ° connection).

In chemistry and pharmacology, all of you are through modification of individual parts of the molecule (by means of a substitution) derived derivatives to the group of phenothiazines.

Properties and classification

Phenothiazines are sensitive to oxidation, slightly water- soluble substances, which on exposure to air and light - promoted by heavy metal ions - easily decompose in solution to discoloration. The next ( unsubstituted ) phenothiazine belonging to the group of phenothiazines substituted derivatives according to its structure are further subdivided into those of chlorpromazine, perphenazine Pecazin and type; also are the azaphenothiazines and thioxanthenes phenothiazines near:

Chlorpromazine - type

This includes the substances with an open side chain at R2:

• Acepromazine,
• Chlorpromazine,
• Levomepromazine,
• Promazine,
• Promethazine,
• Triflupromazine.

The representatives of the Chlorpromazintyps are rather weak antipsychotic effect ( low to medium potency neuroleptics ).

Pecazin type

These include substances having Piperidinylalkyl side chain of R2. In Germany, only the weakly potent thioridazine in the trade. However, a large manufacturer of thioridazine took this neuroleptic end of June 2005 the world from the market because the risk of serious adverse effects appeared stronger than with other neuroleptics.

Perphenazine - type

These are phenothiazines with a piperazinylalkyl side chain on R2:

• Perazine,
• Perphenazine, and
• Fluphenazine.

They work in comparison with chlorpromazine at least equally strong, rather more anti psychotic.

Azaphenothiazines

These have an aza - analog ring system and act the same way as the foregoing. The only representative of this subgroup is the Prothipendyl.

Thioxanthenes

They are the actual phenothiazines also very similar, only the three-ring backbone is formed by thioxanthene.

Important representatives are

• Chlorprothixene,
• Zuclopenthixol / Clopenthixol, and
• Flupentixol.

They differ also in R2: Chlorprothixene has an open, flupentixol and zuclopenthixol have a piperazinylalkyl side chain.

Production

Unsubstituted phenothiazine is prepared industrially by catalyzed reaction of diphenylamine with 2 equivalents of sulfur in the melt. In addition to phenothiazine produced the by-product hydrogen sulfide which is removed in gaseous form. The remaining phenothiazine is purified by vacuum distillation.

Areas of application

They are used medically as

• Neuroleptics (medicines for psychosis )
• Sedatives ( tranquilizers )
• Antihistamines (medicines for allergic reactions)
• Antiemetic / antivertiginous (certain drugs for nausea and dizziness)

Most of phenothiazine preparations come in psychiatry in the treatment of schizophrenia (ie as neuroleptics ) are used. The low-potency promethazine is often used for anxiety and arousal and has proven itself for decades.

Effect

The phenothiazines total effect of non-specific, with a wider range than the butyrophenones or other classes of neuroleptics. Often block a wide range of neurotransmitter receptors, including D2, α1, 5HT2A, H1 and M1 receptors, thus

• Sedation and antipsychotic activity,
• Antiemetic,
• Local anesthetic,
• Ganglionic blocking,
• Anti -adrenergic,
• Anticholinergic and
• Antihistaminic

Effects can occur.

Adverse effects

The side effects of phenothiazines result from the relatively broad spectrum of activity (see in action).

The highly potent substances can by its dopamine receptor blockade induce similar motor disorders such as strong butyrophenones: These include extrapyramidal motor disorders ( EPMS ) Early and tardive dyskinesia, akathisia, and Parkinson-like symptoms.

Some phenothiazines ( esp. of chlorpromazine - type ) can cause disturbances of heat regulation.

Some phenothiazines may cause long QT syndrome and thus lead to fatal cardiac arrhythmias.

History

The history of phenothiazines goes back to the beginnings of organic chemistry in the mid-19th century. 1865 August Kekulé presented on the theory that the carbon atoms in organic compounds in ring systems ( benzene ring) occur. Practical significance had this knowledge, especially in the paint industry. 1876 ​​two dyes methylene blue and thionine were ( Lauths violet) prepared both containing Phenothiazinstruktur. In the coming years, methylene blue was tried as a remedy for malaria, headaches or depression, but could not prevail. In the first half of the 20th century it became quiet around the phenothiazines. In veterinary medicine, it was used as a vermifuge, for the people they were in higher doses to be too toxic. It was only in the 1940s, medical research began again increasingly turn to the phenothiazines. The French pharmaceutical company Rhone- Poulenc discovered phenothiazines with antihistaminic properties. This led in 1950 to the synthesis of neuroleptics ( chlorpromazine ).