Phenothiazines
As phenothiazines a subgroup is thiazines referred to, wherein the central nitrogen - and sulfur -containing thiazine ring, two fused benzene wearing rings. Many are used as drugs , dyes , and insecticides . The pharmaceutically effective phenothiazines have structural chemical features in common with the first neuroleptic to be discovered - chlorpromazine . All phenothiazines have a spatially approximately planar three-ring system which, strictly speaking, bears the name phenothiazine on its own (without substituents ) .
In chemistry and pharmacology , all derivatives derived therefrom by modifying individual parts of the molecule (especially by means of substitution ) belong to the group of phenothiazines .
Properties and classification
Phenothiazines are oxidation-sensitive, poorly water-soluble substances which, when exposed to air and light - promoted by heavy metal ions - easily decompose in solution with discoloration. The substituted derivatives belonging to the group of phenothiazines in addition to (unsubstituted) phenothiazine can be further subdivided according to structural features into those of the chlorpromazine , pecazine and perphenazine types ; In addition, the azaphenothiazines and the thioxanthenes are close to the phenothiazines:
Chlorpromazine type
These include the substances with an open side chain on R 2 :
The representatives of the chlorpromazine type are rather weakly antipsychotic (low to medium potent neuroleptics).
Pecazin type
These include substances with a piperidinylalkyl side chain on R 2 .
In Germany only the weakly potent thioridazine is on the market. The manufacturer Novartis withdrew this neuroleptic from the market worldwide at the end of June 2005 because the risk of serious adverse effects seemed greater than with other neuroleptics.
Perphenazine type
These are phenothiazines with a piperazinylalkyl side chain on R 2 :
- Perazine ,
- Perphenazine , and
- Fluphenazine .
Compared to chlorpromazine, they have at least the same effect, but more of a stronger antipsychotic effect.
Azaphenothiazines
These have an aza-analogous ring system and have the same effect as the aforementioned substances. The only representative of this subgroup is the prostipendyl .
Thioxanthenes
They are also very similar to the actual phenothiazines, only their three-ring skeleton is formed by thioxanthene .
Important representatives are
- Chlorprothixen ,
- Zuclopenthixol / Clopenthixol , and
- Flupentixol .
They also differ in R 2 :
Chlorprothixen has an open side chain , Flupentixol and Zuclopenthixol have a piperazinylalkyl side chain .
Manufacturing
Unsubstituted phenothiazine is produced industrially by the catalyzed reaction of diphenylamine with 2 equivalents of sulfur as an oxidizing agent in the melt. This produces phenothiazine and, as a reduction product , hydrogen sulfide , which is removed in gaseous form. The remaining phenothiazine is purified by vacuum distillation .
- (C 6 H 5 ) 2 NH + 2 S → C 12 H 9 NS + H 2 S
Its derivatives can be prepared in a similar way from p- diamines or aminothiophenols and sulfur.
application areas
They are used medicinally as
- Neuroleptics (anti- psychosis drugs )
- Sedatives (tranquilizers)
- Antihistamines (medicines for allergic reactions)
- Antiemetics / Antivertiginosa (agents against nausea and dizziness)
Most phenothiazine preparations are used in psychiatry for the treatment of schizophrenia (i.e. as neuroleptics ). The low potency promethazine is often used against anxiety and agitation and has been used for decades.
effect
The phenothiazines as a whole are more unspecific, with a broader spectrum than the butyrophenones or other classes of neuroleptics . They often block a number of receptors for neurotransmitters , including D 2 - , α 1 - , 5-HT 2A - , H 1 - and M 1 - receptors, thereby
- Sedation and antipsychotic effects,
- antiemetic ,
- local anesthetic ,
- ganglia blocking ,
- anti- adrenergic ,
- anticholinergic and
- antihistaminic
Effects can arise.
unwanted effects
The side effects of phenothiazines result from the comparatively broad spectrum of activity (see under effect ).
Due to their dopamine receptor blockade, the highly potent substances can trigger motor disorders similar to those of the strong butyrophenones: These extrapyramidal motor disorders (EPMS) include early and late dyskinesia , akathisia and symptoms similar to Parkinson's .
Some phenothiazines (especially of the chlorpromazine type) can cause disorders of thermoregulation.
Some phenothiazines can cause long QT syndrome, leading to fatal arrhythmias.
history
The history of phenothiazines goes back to the beginnings of organic chemistry in the middle of the 19th century. In 1865 August Kekulé put forward the theory that the carbon atoms in organic substances appear in ring systems ( benzene ring ). This knowledge was of practical importance, especially in the paint industry. In 1876 the two dyes methylene blue and thionine ( Lauths violet ) were produced, both of which contain the phenothiazine structure. In the next few years, methylene blue was tried as a remedy for malaria, headaches or depression, but it was not successful. In the first half of the 20th century there was silence about the phenothiazines. In veterinary medicine they were used as wormers , for humans they were considered too toxic in higher doses. It was not until the 1940s that medical research began to increasingly turn to phenothiazines again. The French pharmaceutical company Rhône-Poulenc discovered phenothiazines with antihistamine properties. This led to the synthesis of neuroleptics ( chlorpromazine ) in 1950 .
See also
Butyrophenones , Diphenylbutylpiperidines , Benzamides , Atypical Neuroleptics
Individual evidence
- ↑ a b Science-Online-Lexika: Phenothiazine im Lexikon der Chemie .
- ↑ THIORIDAZINE - Withdrawn due to poor benefit / risk profile , WHO Pharmaceuticals Newsletter 2005, No. 01, accessed November 20, 2016.
- ↑ Otto Lange: The sulfur dyes, their manufacture and use . Springer-Verlag, 2013, ISBN 978-3-662-34052-3 , p. 22 ( limited preview in Google Book search).
- ^ Clemens Lamberth, Jürgen Dinges: Bioactive Heterocyclic Compound Classes Pharmaceuticals . John Wiley & Sons, 2012, ISBN 3-527-66447-5 , pp. 51 ( limited preview in Google Book search).
- ^ H. Schmidt (ed.), Founded by C.-J. Estler: Pharmacology and Toxicology. Schattauer, Stuttgart and New York 2007, p. 225.
- ↑ H. Bangen: History of the drug therapy of schizophrenia. Verlag für Wissenschaft und Bildung, Berlin 1992, pp. 73–77.
