Phenothiazine, complex

The multidrug resistance (mdr) reversing effect of the new phenothiazine complexes were tested on mouse T cell lymphoma cell lines. Trifluoperazine (TFP) was much more effective at the same concentration than verapamil. The efficacy of some metal coordination complexes [TFP-Cu(ll) and TFP-V(IV)] exceeded the action of TFP alone. Chlorpromazine (CPZ) or CPZ-Pt(ll) complex had the same or less effect than verapamil or promethazine (Pz) used as a control. 

Aromatic denitrocyclizations have been used for many years in some well-known synthetic reactions. Probably the best known example is the Turpin synthesis of phenoxazines and similar synthesis of phenothiazines. The classical setup used usually base-catalyzed reactions in polar protic solvents, very often alcohols. In many cases using polar aprotic solvents was found advantageous. Besides the mentioned influence of the H-bonding, better ionization and lower solvation of the nucleophile are also important. Sf Ar reactions proceed through strongly polarized complexes, which are well soluble and highly polarized in polar aprotic solvents. 

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). ... 

The use of urethanes of phenothiazines involving the heterocyclic nitrogen (22, 45) as a means of attaching the side chain is discussed above. Although these intermediates apparently do not possess antipsychotic activity, two compounds of this general class, endowed with somewhat more complex appendages, do exhibit... 

Nowhere, perhaps, is this phenomenon better illustrated than in the phenothiazine class. The earlier volume devoted a full chapter to the discussion of this important structural class, which was represented by both major tranquilizers and antihistamines. The lone phenothiazine below, flutiazin (130), in fact fails to show the activities characteristic of its class. Instead, the ring system is used as the aromatic nucleus for a nonsteroidal antiinflammatory agent. Preparation of 130 starts with formylation of the rather complex aniline 123. Reaction with alcoholic sodium hydroxide results in net overall transformation to the phenothiazine by the Smiles rearrangement. The sequence begins with formation of the anion on the amide nitrogen addition to the carbon bearing sulfur affords the corresponding transient spiro intermediate 126. Rearomatization... 

The electron-transfer reactions between the /3-cyclodextrin (/3-CD) N-substituted phenothiazine derivatives and /3-CD.ATPO (4-acetoxy-2,2,6,6-tetramethyl-1-oxopiperidinium hexachloroantimonate) were found to be influenced by the conformations of the phenothiazine derivatives restricted by the /3-CD cavity. N-Phenylphenothiazine (PPT) and A-phenylethylphenothiazine (PEPT), included by /3-CD, can transfer an electron to the /S-CD.ATP complex. No electron transfer was observed between the /3-CD.A-benzylphenothiazine (/3-CD.BPT) complex under the same conditions. The conformation of the /3-CD.BPT complex is such that the oxidation centre was shielded by the /3-CD wall and the substituent. However, electron-transfer reactions between y-CD.BPT and /3-CD.ATP and nitric acid occurred. ... 

In complex (81), the electron-donating phenothiazine moiety is separated from the Ru(bpy)2 " unit by a triazole bridge that carries a formal negative charge. An investigation of this system shows that such anionic bridges can mediate electron transfer between chromophore and quencher. ... 

Phenothiazines exhibit a complex pharmacological range of action on the CNS and the peripheral nervons system. In addition, they act on the endocrine system. 

The pharmacology of all these neuroleptics is extremely complex. Briefly, phenoth-iazines and related drugs have a calming effect on psychotic patients, without producing excessive sedation. Other central effects include the important antiemetic effect in disease-, drug-, or radiation-induced nausea, but not so much in motion sickness. Butyrophenones are more effective antiemetics than phenothiazines and also potentiate the activity of anesthetics. 

The reduced basicity of phenothiazine nitrogen requires that even acylation proceed via the anion. The amide (34-2) from the methyl thioether (34-1) can be prepared, for example, by sequential reaction with sodium amide and acetic anhydride. Oxidation of that intermediate with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone this affords the phenothiazine (34-3) on hydrolysis of the amide. Complex side chains are most conveniently incorporated in a stepwise fashion. The first step in the present sequence involves reaction of (34-3) as its anion with l-bromo-3-chloropropane to give (34-4). The use of that halide with alkylate piperidine-4-carboxamide (34-5) affords the antipsychotic agent metopimazine (34-6) [35]. 

Finally, the inhibitory effects of phenothiazines on the formation of Of by PMNs have been interpreted as evidence for the participation of calmodulin in the transmission of the signal from the surface of the cell to the oxidase. One action of phenothiazines is to inhibit the effects of the complex of calmodulin and Ca . The activity of the effector molecule, such as phosphodiesterase, which would normally be stimulated by the binary complex of Ca with calmodulin, is not stimulated in the presence of phenothiazines. Jones et al. have shown that in both intact PMNs and in membranous fragments of PMNs stimulated with opsonized zymosan, phenothiazines inhibit the formation of Of. The hierarchy of potency of the various pheno-... 

Even the comparatively unreactive phenoxazine and phenothiazine systems undergo halogenation and nitration with ease and it is normal to prepare monosubstituted derivatives by stepwise procedures rather than by direct electrophilic attack. Indeed, the nitration of phenoxazine is uncontrollable and even N-acylphenoxazines afford a mixture of di- and tetra-nitro products (03CB475). Similarly phenothiazine and nitric acid produce a complex mixture of nitrated sulfoxides and sulfones. Chlorine in DMSO at 40 °C reacts with phenothiazine to yield 3,7-dichlorophenothiazine, whereas cupric chloride gives the 1,7-isomer (76JPR353). Direct bromination of phenoxazine produces a mixture of 3-bromo- and 3,7-dibromo-phenoxazines, while thionyl chloride affords the 1,3,7,9-tetrachloro derivative (60ZOB1893). 

These and other venerable synthetic routes to the tricyclic oxazines and thiazines have been reviewed in detail (B-78MI22701). 2-Hydroxy(or mercapto)-2, 4 -dinitrodiphenylamines readily cyclize to phenoxazines (or phenothiazines) in basic media through elimination of nitrous acid. This is the so-called Turpin reaction, which is complicated by the fact that the intermediate Meisenheimer complexes (251) may undergo a Smiles-type rearrangement so that mixtures of isomeric products are obtained (Scheme 112). 

Monocyclic oxazines and thiazines also function as bases and as very useful synthetic intermediates, particularly for the construction of carbonyl derivatives and as starting points for many complex heterocyclic systems. These properties are illustrated in earlier parts of this chapter. Finally, at a time when man has become acutely aware of the diminution of fossil fuel reserves, phenothiazines have been shown to be potentially valuable in solar energy converters (79MI22701). 

Indeed, photooxidation of MPT in water/ethanol (1/2) leads, as expected from similar experiments with PTH (v. supra), to a complex mixture of products. The main components of the mixture have been separated and identified (22). 3-Hydroxy-10-methyl-phenothiazine (E) is not formed in a singlet oxygen reaction (26) in analogy to the products from the photooxidation of directly excited phenothiazine, the formation of E may be explained by a recombination of the products of reaction 23,... 

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