Phenothiazine ring with

Without additional reagents Phenothiazine ring with rearrangement... 

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. 

This group of drugs is subdivided into three subgroups depending on the type of substitution on the nitrogen atom of the phenothiazine ring. The subgroups are phenothiazines with an aliphatic side chain (chlorpromazine, promazine, triflupromazine), piperazine derivatives (acetophenazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine), and piperidines (mesoridazine, thioridazine). 

The thioxanthenes differ from the phenothiazines by the replacement of nitrogen in the central ring with a carbon-linked side chain fixed in space in a rigid structural configuration. An N,N-dimethyl sulfonamide functional... 

The choice of a cell line to study MDR modulator potency was very important for future potential application in human cancer treatment. PhM (12) that were quite effective in resistant mouse lymphoma cells were only slightly active in drug-resistant human sarcoma cell line MES-SA/Dx5 [198]. The drug-sensitive human sarcoma cell line MES-SA and its multidrug-resistant counterpart MES-SA/Dx5 were applied as a model system for evaluation of MDR modulator activities. Examination performed by the flow cytometric Rhl23 accumulation test demonstrated that the well-known P-gp modulators verapamil (79) and TFP (5) reduced MDR in MES-SA/Dx5 cells. In resistant MES-SA/Dx5 cells, verapamil (79) and TFP (5) restored the drug accumulation pattern which was typical for sensitive cells. However, the effectiveness of PhM (12) was very low. The most active compounds were derivatives with an H atom at position 2 of the phenothiazine ring, followed by Cl-substituted and CF3-substituted compounds. 

The selection of the material dealt with in this section has been made on the basis of two criteria (i) to what extent the reactivity of a substituent is influenced by the phenothiazine ring and ii) the preparative value of a given reaction as a route to important phenothiazine derivatives. 

A unique series of neuroleptics results from the replacement of the nitrogen within the phenothiazine ring system with a methine carbon. The introduction of the double bond within the propylamino chain provides for geometric isomers. The geometry, wherein the... 

Acetylfluphenazine (VI, Figure 5) was hydrolyzed enzymatically to fluphenazine (I) iui, vitro by homogenates of small intestinal mucosa, liver, and brain from either the rat or the monkey.29 (See also section 7). When fluphenazine was incubated with a "microsomal and soluble" fraction of rat livers, hydroxylation on the phenothiazine ring was observed. 30 sulfoxide was not de-... 

The first compound containing a phenothiazine ring, 3,7-diamino-phenazathionium chloride, was obtained in 1876 by Lauth (1876CB1035). Bernth-sen synthesized the parent phenothiazine in 1883, by heating diphenylamine with sulfur (1883CB2896). 

In the synthesis of phenothiazines, ring closure successfully rivals with other reactions involving functional group insertion, removal or modification, and the scope of this review is to summarize the cyclization reactions known to produce the phenothiazine ring based on a retrosynthetic analysis scheme. Although we tried to ensure the coverage of all known synthetic pathways, the literature references are, however, limited to the most significant examples (the same procedure, e.g. thionation, has been used without relevant modifications by a spate of authors). 

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