Thioxanthene Derivatives

Thioxanthenes differ structurally from phenothiazine in that the nitrogen atom of the central ring of the tricyclic system is replaced by carbon, which is joined to a side chain with a double bond. Their pharmacological action is similar to the corresponding phenothiazine analogues. They have the exact mechanism of action and an analogous effect on the CNS. Drugs of this series differ from one another by quantitative indexes.

Chlorprothixene: Chlorprothixene, 2-chloro-9[(1-dimethylamino)-3-propyliden]thioxan-thene (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 [34-36], 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).

6.2.2 6.2.3

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. Synonyms of chlorprothixene are clothixene and tarasan.

Thiothixene: Thiothixene, N,N-dimethyl-9-[3-(4-methyl-1-1piperazinyl)propyliden]-thiox-anten-2-sulfonamide (6.2.14), is synthesized from 9H-thioxantene, which is reacted with chlorosulfonic acid to give 9H-thioxanten-2-sulfonic acid (6.2.8). This is transformed into 2-dimethylaminosulfonyl-9H-thioxantene (6.2.9) by reaction of 6.2.8 with thionyl chloride and dimethylamine. The reaction of 2-dimethylaminosulfonyl-9H-thioxantene (6.2.9) with butyllithium and then with methylacetate forms 9-acetyl-2-dimethylaminosulfonyl-9H-thiox-antene (6.2.10). Aminomethylation of the resulting product with dimethylamine and formaldehyde gives 9-(2-dimethylamineopropionyl)-2-dimethylaminosulfonyl-9H-thioxan-tene (6.2.11). Reacting this with 1-N-methylpiperazine results in a substitution of the dimethylamine group in the acylic part of the molecule with a N-methylpiperazine group, giving the product (6.2.12). The carbonyl group of the product is reduced to a secondary hydroxyl group using sodium borohydride followed by the dehydration of the product (6.2.13) with the help of phosphorous oxychloride to give the desired thiothoxene (6.2.14) [37-40].

Thiothixene displays a specific chemical and pharmacological similarity to piperazine derivatives of the phenothiazine series, and is used for treating psychotic disorders. The indications for using thiothixene are the same as for chlorprothixene. Synonyms of this drug are orbinamon, navane, and others.

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