Chlorprothixene hydrochloride Chemical Properties

Melting point:

224-226?C

storage temp. 

2-8°C

solubility 

Soluble in water and in alcohol, slightly soluble in methylene chloride.

CAS DataBase Reference

6469-93-8

Safety Information

Hazard Codes 

Xn

Risk Statements 

20/21/22

Safety Statements 

36

RIDADR 

UN 2811 6.1/PG 3

WGK Germany 

3

RTECS 

XO0610000

HazardClass 

6.1(b)

PackingGroup 

III

Chlorprothixene hydrochloride Usage And Synthesis

Chemical Properties

Pale Yellow Solid

Originator

aractan, Roche, France ,1960

Uses

Antipsychotic.

Uses

Neuroleptic;D2 dopamine receptor antagonist

Uses

Chlorprothixene hydrochloride has been used to study its exposure effects on learning and memory of rats.

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.

Therapeutic Function

Tranquilizer

General Description

Chlorprothixene is a neuroleptic drug, which belongs to thioxanthene group. It has anticholinergic effects. Chlorprothixene might be associated with obstructive jaundice and parkinsonism. It is used to treat psychosis.

Biological Activity

chlorprothixene (hydrochloride) is an antagonist of dopamine receptor and histamine receptors [1]. chlorprothixene is also an inhibitor of gabaa receptor [2]. all of these three receptors are implicated in many neurological processes, including motivation, pleasure, cognition, memory and learning.

in vitro

chlorprothixene exihibited strong binding affinities to dopamine and histamine receptors, the ki values of d1, d2, d3, d5 and h1 were 18nm, 2.96 nm, 4.56 nm, 9 nm and 3.75 nm, respectively. chlorprothixene showed little affinity to h3 with the ki value of >1000 nm[1]. in cos-7 cells transiently expressed rat 5-ht7 receptors and hek-293 cells stably transfected with rat 5-ht6, the ki values of chlorprothixene were 5.6 nm and 3 nm, respectively [3]. in vero 76 cells, chlorprothixene treatment inhibited sars-cov replication, with ic50 of 16.7 μm for urbani strain, 13.0 μm for frankfurt-1, 18.5 μm for chuk-w1 and 15.8 μm for toronto-2 [4].

in vivo

in rat brain depressing the release of hypothalamic and hypophyseal hormones, chlorprothixene blocked postsynaptic mesolimbic dopaminergic d1 and d2 receptors [5]. chlorprothixene treatment restored normal ceramide concentrations in murine bronchial epithelial cells, reduced inflammation in the lungs of mice with cystic fibrosis (cf) and prevented infection with pseudomonas aeruginosa [6].

References

[1] von coburg y, kottke t, weizel l, et al. potential utility of histamine h 3 receptor antagonist pharmacophore in antipsychotics[j]. bioorganic & medicinal chemistry letters, 2009, 19(2): 538-542.
[2] squires r f, saederup e. clozapine and several other antipsychotic/antidepressant drugs preferentially block the same ‘core’fraction of gaba a receptors[j]. neurochemical research, 1998, 23(10): 1283-1290.
[3] roth b l, craigo s c, choudhary m s, et al. binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors[j]. journal of pharmacology and experimental therapeutics, 1994, 268(3): 1403-1410.
[4] barnard d l, day c w, bailey k, et al. is the anti-psychotic, 10-(3-(dimethylamino) propyl) phenothiazine (promazine), a potential drug with which to treat sars infections: lack of efficacy of promazine on sars-cov replication in a mouse model[j]. antiviral research, 2008, 79(2): 105-113.
[5] gey k f, pletscher a. influence of chlorpromazine and chlorprothixene on the cerebral metabolism of 5-hydroxytryptamine, norepinephrine and dopamine[j]. journal of pharmacology and experimental therapeutics, 1961, 133(1): 18-24.
[6] becker k a, riethmuller j, luth a, et al. acid sphingomyelinase inhibitors normalize pulmonary ceramide and inflammation in cystic fibrosis[j]. american journal of respiratory cell and molecular biology, 2010, 42(6): 716-724.]

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