Synthesis, Isolation, and Characterization of Two Stereoisomeric Ring Sulfoxides of Thioridazine

Juenge, Eric C.; Wells, Clyde E.; Green, Donald E.; Forrest, Irene S.; Shoolery, James Ν.

doi:10.1002/jps.2600720610

Cited by 24 publications

(9 citation statements)

References 15 publications

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“…100 : 7 and Merck silica gel 60 F 254 Al sheets (0.2 mm). For all compounds (except 4, which had not been investigated in previous reports [22] [36]), the elution order was as reported. Retention factors (R f values; see Table) were marginally different from those reported, which is probably due to the different silica gel plates employed.…”

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confidence: 98%

“…Indeed, the reported melting point for 3 (128 ± 1318) lies in the upper range of the broad melting point of diastereoisomeric 2 (113.5 ± 128.58 [21]). In addition to the lack of useful procedures for the synthesis of 3, there are currently no procedures for the synthesis of 4 through direct oxidation of the parent compound, and there is only one previously reported procedure for the synthesis of 2 from 1 [22].…”

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confidence: 98%

“…Synthesis of Metabolite 2. Oxidation of the ring sulfide S-atom of 1 could be achieved by a previously reported oxidative method involving NaNO 2 and a few drops of concentrated HCl [22], which generated rac-2 in yields of at least 94%. Nevertheless, upon slight modification of the reported reaction conditions, we were able to increase the yield of 2 to b 96%.…”

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confidence: 99%

“…TLC Analysis [24] [28]. The TLC method used for the analysis of thioridazine (1) and its metabolites 2 ± 4 followed that previously reported [22] [35], using acetone/12n aq. NH 4 OH soln.…”

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Facile Syntheses of the Three Major Metabolites of Thioridazine

Morrow

Millership

Collier

2005

Helvetica Chimica Acta

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Efficient, mild syntheses of the three major metabolites 2 ± 4 of the important antipsychotic drug thioridazine (1) have been developed. The cardiotoxic metabolite 2 with a ring sulfoxide moiety was prepared in 96% yield by oxidation of 1 with NaIO 4 under acidic conditions. Four different procedures were elaborated for the selective side-chain sulfide oxidation of 1 to mesoridazine (3), giving rise to yields of up to 91%. Finally, sulforidazine (4) was synthesised via oxidation of the sulfoxide 3 in the presence of either KMnO 4 or t-BuOOH under basic conditions. Except for the oxidation with t-BuOOH, all reactions took place under mild conditions within a few minutes, were nicely reproducible, and afforded medium-to-high yields of the desired products, which could be readily purified by column chromatography.Introduction. ± Thioridazine (1) 1 ) is a chiral, tricyclic drug used in racemic form for the treatment of schizophrenia and other psychiatric disorders, and produces few extrapyrimidal side effects (a regular side effect in antipsychotic therapy) [1 ± 2]. Like all other antipsychotic agents, the ability of 1 to alleviate psychotic symptoms is attributed to antagonistic blocking of central dopamine receptors, which compensates for the overactivity of this neurotransmitter [3]. However, the individual enantiomers of 1 have been shown to produce significantly different pharmacologic effects. Several authors have reported a difference in the distribution of the enantiomers in blood plasma and in various human tissues [4 ± 6]. Furthermore, it has been shown that ()-(R)-thioridazine ((R)-1; see Scheme) has a 2.7-times higher affinity than the (À)-(S)-isomer for the important D 2 receptors, which are most strongly related to alleviation of psychotic symptoms in rat brain [3].It has been recognised that the pharmacologic effects of thioridazine therapy are not only attributed to the parent drug, but also to the major metabolites: the ring sulfoxide 2, the side-chain sulfoxide mesoridazine (3), and the side-chain sulfone sulforidazine (4). All these compound are known to significantly contribute to the overall pharmacological profile of thioridazine-based drug therapy [7 ± 20]. In fact, compounds 3 and 4 have been shown to be ca. 50% more potent than the parent drug 1 [7 ± 10], and the ring sulfoxide 2, although not considered to contribute to the observed antipsychotic activity, is reported to be the major cause of cardiotoxic side effects associated with the administration of 1 [14 ± 20].Despite the importance of the metabolites 2 ± 4, there is still minimal information regarding the pharmacologic and pharmacokinetic effects of the isomers of these compounds, and there are currently only a few useful methods for their synthesis from

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Facile Syntheses of the Three Major Metabolites of Thioridazine

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2005

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“…Conventional preparation methods for phenothiazine sulfoxide have been reported. [4][5][6][7][8][9] The yields of these methods are not sufficient, and the phenothiazine derivatives reported have been limited to simple structural phenothiazine derivatives and drugs produced at an early stage of development.…”

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Preparation of Metabolites by Chemical Reaction: Conversion of Antipsychotic Phenothiazines to their Sulfoxides and Tertiary Amino Cyclic Antidepressants to their N-Oxide with Hydrogen Peroxide Using Titanosilicate Catalyst

Ogamo

Fukumoto

2004

JOURNAL OF HEALTH SCIENCE

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The aim of this study was to establish a preparation method needed to analyze the metabolites of an analytical procedure for antipsychotic phenothiazines and tertiary amino cyclic antidepressants by chemical reaction. These drugs were oxidized to their sulfoxide and N-oxide, respectively, with hydrogen peroxide using titanosilicate as the catalyst. An acidic medium (pH 3.0) containing 20% methanol was found to be optimal for the preparation of phenothiazine sulfoxide, and an alkaline medium (pH 10.5) containing 50% methanol was optimal for the preparation of the Noxide of tertiary amino cyclic antidepressants. Each preparative scale reaction (2 mmol) was carried out and the crystallized product of each oxide was obtained. The amount of hydrogen peroxide needed to obtain the best yields of sulfoxide was 1.3-2.0 times the molar equivalent of the phenothiazines. The purities of the prepared crystallized product of the phenothiazine sulfoxides were good except for periciazine sulfoxide. The amounts of hydrogen peroxide needed to obtain the best yields of N-oxide were 4-5 times the molar equivalent of tertiary amino cyclic antidepressants. The purities of the crystals of each N-oxide were 99.5-100%. The characteristic mass fragment ions of each prepared oxide that were distinguishable as the N-oxides from parent drug could be confirmed when the collisional energy was decreased to 10 eV. 1 H-and 13 C-NMR spectral data confirmed the structure of the prepared mianserin N-oxide to be 2-oxide. In conclusion, a simple and rapid preparation method for oxide metabolites of phenothiazines and tertiary amino cyclic antidepressants available as analytical standards was established.

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