Phenothiazine

Description

Phenothiazine was initially synthesized in 1883 by Bernthsen. It was the basis for the development of other drugs including the phenothiazine class of antipsychotics or neuroleptics. Phenothiazines are the largest class of neuroleptics and include agents such as chlorpromazine, thioridazine, and prochlorperazine. In 1933, a derivative of phenothiazine, promethazine, was synthesized. It was found to have much more significant sedative and antihistaminic effects than previous derivatives of phenothiazine and it was used to induce sedation for surgical patients. After promethazine was developed, a series of agents, including chlorpromazine, was synthesized and tested in France at a military hospital by the French physician Laborit. Laborit found that chlorpromazine induced calm in patients and had other effects that might be useful clinically. Chlorpromazine, known colloquially as ‘Laborit’s drug’ was released into the market in 1953 after a trial published in 1952 showed efficacy in treatment of psychosis in 38 individuals who received daily injections of chlorpromazine. Chlorpromazine is the prototypical drug for the phenothiazine class of antipsychotics. The phenothiazines are classified as low-potency antipsychotics and have more side effects at standard doses than the newer agents used as neuroleptics. For example, they are more anticholinergic and have more extrapyramidal effect than newer agents.

Description

Phenothiazine, a heterocyclic compound that contains ring nitrogen and sulfur atoms, was first made in 1883 when A. Bernthsen fused diphenylamine with sulfur. By 1954, its chemistry was rich enough to be described in?Chemical Reviews?.?Phenothiazine and its derivatives (notably chlorpromazine, or Thorazine) are marketed as antipsychotic and antihistaminic drugs.

Chemical properties

yellow or pale green powder

Chemical properties

Phenothiazine is a greenish-yellow to greenish-gray crystalline substance. Slight odor and taste.

The Uses of Phenothiazine

Phenothiazines are neuroleptic agents that affect a variety of receptors including dopaminergic receptor sites. Phenothiazines are used to treat psychosis including schizophrenia; violent, agitated, disturbed behavior; and mania secondary to bipolar disorder. Other uses include treatment of pain, headache, hiccups, acute severe anxiety, idiopathic dystonia, withdrawal, taste disorders, leishmaniasis, acute intermittent porphyria, and alleviation of nausea and vomiting. Phenothiazines allow smoother induction of anesthesia, potentiate anesthetic agents, and treat behavioral symptoms secondary to Alzheimer disease and senile dementia. Some phenothiazines exert an antipruritic effect and are useful for the treatment of neurodermatitis and pruriginous eczema, and relieve psychogenic itching.

The Uses of Phenothiazine

A key component of antipsychotic and antihistaminic drugs.

The Uses of Phenothiazine

Employed in the preparation of carbazoles and piperazines,1 and charge-transfer semiconducting complexes.2

The Uses of Phenothiazine

A rigid, tricyclic thiazine useful as an electron donor.

The Uses of Phenothiazine

Insecticide; manufacture of pharmaceuticals.

What are the applications of Application

Phenothiazine is a rigid, tricyclic thiazine useful as an electron donor

Definition

ChEBI: The 10H-tautomer of phenothiazine.

brand name

Nemazine (Parke-Davis).

Synthesis Reference(s)

Synthesis, p. 506, 1974 DOI: 10.1055/s-1974-23359

General Description

Light green to steel-blue powder. Acquires a greenish-brown tint under exposure to sunlight.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Phenothiazine is slowly decomposed by sunlight. . Organosulfides are incompatible with acids, diazo and azo compounds, halocarbons, isocyanates, aldehydes, alkali metals, nitrides, hydrides, and other strong reducing agents. Reactions with these materials generate heat and in many cases hydrogen gas. Many of these compounds may liberate hydrogen sulfide upon decomposition or reaction with an acid.

Fire Hazard

Flash point data for Phenothiazine are not available, but Phenothiazine is probably combustible.

Flammability and Explosibility

Non flammable

Safety Profile

Poison by intravenous route. Moderately toxic to humans by ingestion. Experimental reproductive effects. An insecticide. Large doses, i.e., heavy exposure, may cause hemolytic anemia and toxic degeneration of the liver. Can cause skin irritation and photosensitization. Dangerous; when heated to decomposition or on contact with acid or acid fumes it emits hghly toxic fumes of SOx and NOx.

Potential Exposure

Phenothiazine is used as an insecticide; as a base for the manufacture of tranquilizers; as anthelmintic in medicine and veterinary medicine; it is used widely as an intermediate in pharmaceutical manufacture; polymerization inhibitor, antioxidant.

Environmental Fate

Physicochemical Properties
Phenothiazine has the standard formula S(C6H4)2NH and includes a tricyclic structure that is related to the thiazines. Thiazines are used in the manufacture of synthetic dies.
Chlorpromazine
Chlorpromazine is a white to off-white substance (both the base and the hydrochloride salt) that is a powder or waxy solid as a base and a crystalline powder as the hydrochloride. Chlorpromazine is odorless or has a slightly amine-like odor. It has a melting point of 56–58 °C and in the basic form is practically insoluble in water, soluble in alcohol, and less soluble in chloroform and ether. It is freely soluble in dilute mineral acids. As the hydrochloride salt, chlorpromazine is soluble in water, less soluble in alcohol and chloroform, and insoluble in ether. A 10% aqueous solution has a pH of 3.5–4.5.

Shipping

UN3077 Environmentally hazardous substances, solid, n.o.s., Hazard class: 9; Labels: 9-Miscellaneous hazardous material, Technical Name Required

Purification Methods

Crystallise it from *benzene, toluene, hexane or Me2CO (charcoal) after boiling for 10minutes under reflux. Filter the crystals off and dry them in an oven at 100o, then in a vacuum desiccator over paraffin chips. Also recrystallise it twice from water and dry it in an oven at 100o for 8-10hours. It sublimes at 130o/1mm and has UV with at 253nm in heptane. [Beilstein

Toxicity evaluation

Phenothiazines primarily block postsynaptic neurotransmission by binding to dopamine (D1 and D2), muscarinic, histamine H1, and serotonergic 5-HT2 receptors. Phenothiazines also possess peripheral adrenergic receptor blockade and quinidine-like cardiac effects. Phenothiazines may lower the seizure threshold.

Incompatibilities

Organosulfides are incompatible with strong acids and acid fumes; elevated temperatures; sulfur oxides and nitrogen oxides can be produced. Contact with strong reducing agents such as hydrides; azo and diazo compounds, halocarbons, isocyanates can generate heat and may form explosive hydrogen gas

Waste Disposal

Dissolve in combustible solvent and spray into incinerator equipped with afterburner and scrubber. In accordance with 40CFR165, follow recommendations for the disposal of pesticides and pesticide containers. Must be disposed properly by following package label directions or by contacting your local or federal environmental control agency, or by contacting your regional EPA office.