Phenothiazines, 10-alkyl

In a similar vein, the amino group in sulfide 14 (obtained presumably by an aromatic displacement reaction) is first converted to the bromide by Sandmeyer reaction to give 25. Reduction of the nitro group (16) followed by cyclization gives the substituted phenothiazine. Alkylation with the familiar halide (3) affords dimethothiazine (18). ... 

Of the several syntheses available for the phenothiazine ring system, perhaps the simplest is the sulfuration reaction. This consists of treating the corresponding diphenylamine with a mixture of sulfur and iodine to afford directly the desired heterocycle. Since the proton on the nitrogen of the resultant molecule is but weakly acidic, strong bases are required to form the corresponding anion in order to carry out subsequent alkylation reactions. In practice such diverse bases as ethylmagnesium bromide, sodium amide, and sodium hydride have all been used. Alkylation with (chloroethyl)diethylamine affords diethazine (1), a compound that exhibits both antihista-minic and antiParkinsonian activity. Substitution of w-(2-chloroethyl)pyrrolidine in this sequence leads to pyrathiazine (2), an antihistamine of moderate potency. 

The parent drug of this series, promazine (24), was prepared originally as an antihistamine. Following the identification of the more potent chloro analog as an antipsychotic, it too came into use for that indication. The drug is prepared by straightforward alkylation of phenothiazine with w-C3-chloropropyl)di-methylamine by means of sodium hydride in xylene. ... 

Chlorpromazine (33) can probably be considered the prototype of the phenothiazine major tranquilizers. The antipsychotic potential of the phenothiazines was in fact discovered in the course of research with this agent. It is of note that, despite the great number of alternate analogs now available to clinicians, the original agent still finds considerable use. The first recorded preparation of this compound relies on the sulfuration reaction. Thus, heating 3-chlorodiphenylamine (30) with sulfur and iodine affords the desired phenothiazine (31) as well as a lesser amount of the isomeric product (32) produced by reaction at the 2 position. The predominance of reaction at 6 is perhaps due to the sterically hindered nature of the 2 position. Alkylation with w-C3-chloropropyl)dimethylamine by means of sodium amide affords chlorpromazine (33). ... 

Sulfuration of the methoxy analog of 30 similarly gives a mixture of the desired 2-substituted phenothiazine (35) and byproduct (36). Alkylation of 35 as above affords methoxypromazine (37)... 

Alkylation of phenothiazine with l-chloro-2-methyl-3-bromopropane affords the methylated analog (80) of the intermediate above. Use of this halide to alkylate the piperazine... 

The most complex side chain of the piperazine phenothiazines is to be found on chlorimpiphenine (86). The side chain is prepared by first alkylating monocarbethoxypiperazine with the chlorobenzimidazole 83 [itself attainable by alkylation of methylbenzimidazole with a dihalide). Removal of the carbethoxy group affords the substituted piperazine, 85. Alkylation of this base with the chloropropyl phenothiazine, 58, affords finally the desired compound (86). ... 

Replacement of the terminal nitrogen of the piperazine by carbon is said to enhance the antiemetic activity of the phenothiazines at the expense of the other pharmacologic effects. The simplest compound in this series, pipamazine (88), is prepared by alkylation of nipecotamide (87) with the chloropropyl phenothiazine (58). Preparation of the analogous sulfoxide begins with acetylation of the thiomethyl compound, 89 [prepared by a route... 

Alternately, the N-acylated derivative of the substituted phenothiazine (112) is oxidized to the corresponding sulfoxide by means of periodic acid. Saponification (113) followed by alkylation with the above side chain affords thioridazine (114)... 

Alkylated sulfonamide groups have proven useful additions to the phenothiazine nucleus. The same seems to hold true in the thioxanthene series. Chlorosulfonation of the benzoic acid, 38, followed by displacement with dimethylamine affords the sulfonamide, 39. This is then taken on to the substituted thioxanthone (41) by the sequence of steps shown above Grignard condensation followed by dehydration gives thiothixine (42). 

The phenothiazine duoperone (5) combines structural elements found in phenothiazine and buty-rophenone antipsychotic agents. Alkylation of substituted piperidine 1 with 3-chloropropanol affords the intermediate 2 treatment of this with thionyl chloride converts the terminal hydroxyl to chloride. Alkylation of the phenothiazine 4 with halide 3 affords the antipsychotic agent duoperone (5) [1]. 

The two principal categories of compounds studied have been diaryl or aryl alkyl sulphones (not dialkyl sulphones, which are polarographically not reducible) and S-dioxides of certain heterocyclic compounds, such as thiophene (also benzo- and dibenzothiophenes) and phenothiazines. The first named have half-wave potentials in the region of — 2.0 V, the thiophene dioxides near — 1.0 V. Some examples of each category may be given. 

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