Chlorprothixene

Description

In 2002, the American Association of Poison Control Centers’ Toxic Exposure Surveillance System reported 5224 human exposures to phenothiazines, thioxanthenes, and other neuroleptic medications; 3691 were in adults and 808 in children. Unintentional and intentional exposures accounted for 43.7 and 47.8%, respectively. There were 417 (8.0%) adverse drug reactions reported. Thioxanthenes are chemical compounds in which the oxygen atom in xanthene is replaced with a sulfur atom. They are also related to phenothiazines. Several derivatives are used as typical antipsychotics in the treatment of schizophrenia and other psychoses. The thioxanthenes, as a class, are closely related chemically to the phenothiazines. The major structural difference is that the nitrogen at position 10 in the phenothiazines is replaced by a carbon atom with a double bond to the side chain, as shown in the chemical structure of flupenthixol, which has a double-bonded carbon in the number 10 position. Clopenthixol is a typical antipsychotic drug of the thioxanthenes class and a racemic mixture of cis and trans isomers. Zuclopenthixol, the pure cis isomer, has been much more widely used. Both drugs are equally effective as antipsychotics and have similar adverse effect profiles, but clopenthixol is half as active on a milligram-to-milligram basis and appears to produce more sedation in comparison.

Originator

aractan, Roche, France ,1960

Uses

muscle relaxant (skeletal)

Uses

Thioxanthenes are used as neuroleptic agents, antipsychotics, and major tranquilizers in the treatment of psychosis, including schizophrenia, senile psychosis, pathological jealousy, and borderline personality disorder. Other uses include the treatment of pain, postoperative neuralgia, sedation, anxiety neurosis, childhood behavior problems, and depression. The maximum therapeutic daily oral dose for chlorprothixene, flupenthixol, and thiothixene is 600, 224, and 60 mg, respectively; the maximum intramuscular doses are 200 mg day^-1, 100 mg weekly, and 30 mg day^-1, respectively. Some thioxanthenes and thioxanthenones have shown signs of possible human therapeutic potential against tumors in mice and in vitro assays, and some thioxanthenes have been shown to have cytotoxic and antimicrobial activities.
Chlorprothixene is primarily indicated in conditions such as agitation, mania, psychosis, schizophrenia, and can also be given in adjunctive therapy as an alternative drug of choice for anxiety and herpetic neuralgia. Flupenthixol (HCl and decanoate) is primarily indicated in conditions such as depression, muscle spasms of varied etiology, pain, personality disorder, postoperative nausea and vomiting, psychosis, relief of discomfort in mild urinary tract infections, and schizophrenia. Flupenthixol is also seen to possess powerful antibacterial activity both in vitro and in vivo in mouse experiments. It is bacteriostatic in vitro both against gram-positive and gram-negative bacteria. Thiothixene is used in the management of schizophrenia. It has not been evaluated in the management of behavioral complications in patients with mental retardation.
Zuclopenthixol is primarily indicated in conditions such as dementia, to enhance permeation of subcutaneous or intramuscular injections, labyrinthine disorders, prolactinoma, psychosis, schizophrenia, and second trimester abortion. It is also used in the treatment of acute bipolar mania.

Uses

Chlorprothixene has an antipsychotic and sedative action. It has expressed antiemetic activity. It is used in various psychoses, schizophrenia, reactive and neurotic depression with prevalent anxious symptomatology, and in conditions of excitement associated with fear and stress. It may be used in small doses as a sedative agent in neurosis.

Definition

ChEBI: (Z)-chlorprothixene is a chlorprothixene in which the double bond adopts a (Z)-configuration. It is an enantiomer of an (E)-chlorprothixene.

Manufacturing Process

Chlorprothixene may be prepared as described in US Patent 2,951,082. Magnesium turnings, 4.86 g (0.2 g-atom) was placed in a 500 ml reaction flask fitted with a mercury sealed stirrer, reflux condenser and a dropping funnel. Tetrahydrofuran, 50 ml and calcium hydride, 500 mg, were added. Ethyl bromide, 2.18 g and a crystal of iodine then were added. A vigorous reaction set in that evolved sufficient heat to induce refluxing. After 5 minutes, a solution of 3-dimethylaminopropyl chloride (dried over calcium hydride) in 50 ml of tetrahydrofuran was added to the refluxing solution at such a rate that gentle refluxing was maintained. The addition required 25 minutes.
The reaction mixture was stirred at reflux for an additional 30 minutes when nearly all of the magnesium had dissolved and determination of magnesium in an aliquot of the solution showed that an 82% yield of Grignard reagent had been obtained. The reaction mixture was cooled in an ice bath and stirred while 24.67 g (0.1 mol) of 2-chlorothiaxanthone was added over a period of 10 minutes. The reaction was stirred at room temperature for 30 minutes then allowed to stand overnight in the refrigerator. The tetrahydrofuran was evaporated at 50°C under reduced pressure. Benzene, 150 ml, was added to the residue.
The mixture was hydrolyzed in the cold by the dropwise addition of 50 ml of water. The benzene layer was separated by decantation and the gelatinous precipitate washed with two 100 ml portions of benzene.
The precipitate was then mixed with diatomaceous earth, collected on a filter, and washed with water and extracted with two 100 ml portions of boiling
benzene. The aqueous filtrate was extracted with 50 ml of benzene, the combined benzene extracts washed with water and evaporated to dryness under reduced pressure. The crystalline residue, MP 140° to 147°C, weighed 30.8 g. Recrystallization from a mixture of benzene and hexane gave 27.6 g (83%) of 2-chloro-10-(3-dimethylaminopropyl)-10-hydroxythiaxanthene, MP 152° to 154°C. Analytically pure material from another experiment melted at 153° to 154°C.
2-Chloro-10-(3-dimethylaminopropyl)-10-hydroxythiaxanthene, 3.34 g (0.01 mol) obtained as described was dissolved in 15 ml of dry, alcohol-free chloroform. Acetyl chloride, 2.36 g (0.03 mol) was added and the clear yellow solution was refluxed for one hour in a system protected by a drying tube. The solvent then was evaporated on the steam bath under reduced pressure and the residue dissolved in absolute alcohol. The hydrochloride of 2-chloro- 10-(3-dimethylaminopropylidene)-thiaxanthene was precipitated by the cautious addition of absolute ether. After drying at 70°C the yield of white crystalline 2-chloro10-(3-dimethylaminopropylidene)-thiaxanthene hydrochloride, MP 189 to 190°C (to a cloudy melt), was 3.20 g (90%). This material is a mixture of geometric isomers.
Trans-2-chloro-9-(ω-dimethylamino-propylidene)-thioxanthene [MP 98°C, MP of the hydrochloride 225°C (corr.)], is a valuable medicinal agent, being used as a tranquilizer and antiemetic agent, whereas the corresponding cis isomer (MP 44°C, MP of the hydrochloride 209°C) is not useful for these indications, as described in US Patent 3,115,502, which describes procedures for conversion of the cis to the trans form.

brand name

Taractan (Roche).

Therapeutic Function

Tranquilizer

Synthesis

Chlorprothixene, 2-chloro-9[(1-dimethylamino)-3-propyliden]thioxanthene (6.2.7), has been proposed to synthesize starting from 2-chlorothixantone (6.2.3). The initial 2-chlorothixantone (6.2.3) is prepared from 2-mercaptobenzoic acid, the reaction of which with 1-bromo-4-chlorobenzene forms 2-(4-chlorophenylthio)benzoic acid (6.2.1), which upon reaction with phosphorous pentachloride transforms into acid chloride (6.2.2), and further undergoes intramolecular cyclization with the use of aluminum chloride to give 2- chlorthioxantone (6.2.3) [32]. An alternative way of making 2-chlorthioxantone (6.2.3) is by making 2-(4-chlorophenylthio)benzoic acid (6.2.1) by reacting 2-iodobenzoic acid with 4- chlorothiophenol [33]. The resulting 2-chlorthioxantone (6.2.3) is reacted as a carbonyl component with either 3-dimethylaminopropylmagnesiumbromide [33], or with allylmagnesiumbromide [34¨C36], giving the corresponding tertiary alcohol (6.2.4) or (6.2.5). Dehydration of the first is accomplished by acylation of the tertiary hydroxyl group using acetyl chloride and the subsequent pyrolysis of the formed acetate, which leads to the desired chlorprothixene (6.2.7).
Dehydration of the tertiary alcohol (6.2.5) is accomplished by chlorination of the tertiary alcohol group by thionyl chloride, forming the diene 2-chloro-9-(3-propen-1- iliden)thioxanthene (6.2.6), the addition to which of dimethylamine at high temperature forms the desired chlorprothixene (6.2.7).

Environmental Fate

Long-range transport: handling of thioxanthenes should only be performed by personnel trained and familiar with handling potent active pharmaceutical ingredients. In case of handling, avoid inhalation and contact with skin, eyes, and clothing, as these materials may be an irritant. These substances are considered nonhazardous for transport.

Toxicity evaluation

Thioxanthenes work primarily by blocking postsynaptic dopamine-mediated neurotransmission by binding to dopamine (DA-1 and DA-2) receptors. In addition to significant antidopaminergic action, the thioxanthenes also possess weak anticholinergic and serotonergic blockade, moderate a-adrenergic blockade, quinidine-like effects, and depress the release of most hypothalamic and hypophyseal hormones. Thioxanthenes may also inhibit presynaptic dopamine autoreceptors. The concentration of prolactin is increased due to blockade of prolactin inhibitory factor, which inhibits the release of prolactin from the pituitary gland. Chlorprothixene also inhibits the medullary chemoreceptor trigger zone to produce an antiemetic effect; and is thought to cause an indirect reduction of stimuli to the brain stem reticular system to produce a sedative effect.