Phenothiazines and Related Compounds

Phenothiazmes and Related Compounds.—A paper dealing with the laser photolysis (347.1 nm) of phenothiazine (pth) in methanolic and aqueous sodium lauryl sulphate has appeared. An interesting aspect of this work is the study of a new type of redox reaction involving triplet states of metal ions that have suitable reduction potentials, e.g. Cu + or Eu +, as the reducing agents  

New evidence, obtained by e.s.r. spectroscopy, suggests that the dye-sensitized or direct light-induced photoxidation of phenothiazine is initiated by an electrophilic attack of singlet oxygen on the unshared electron pair of nitrogen, to give the hydroperoxide (77). Subsequently, depending upon the reaction conditions, the 0—0 or N—O bonds in (77) are cleaved, to yield phenothiazine nitroxide or a neutral phenothiazinyl radical. 

Bromination of 3,7-dibromo-lO-alkyl-phenothiazines, e.g. (78), in acetic acid gives purple radical-cations, e.g. (80). On subsequent heating in the same solvent, these radical cations undergo electron transfer with bromide ions to form the parent phenothiazines, e.g. (78), or are irreversibly dealkylated to yield (79) and, hence, 1,3,7,9-tetrabromophenothiazine, by the action of molecular bromine produced in the previous redox reaction. 

In a continued study of A-alkyl- and iSW-dialkyl-suIphilimines, vmious compounds of type (81) have been prepared (see Vol. 3, p. 725), and the reactions 

Additional evidence has been presented in support of hydro-aromatic species, e.g. (82), as intermediates in the thermolysis of aryl 2-azidophenyl sulphides, leading to phenothiazines (Vol. 2, p. 780). A successful synthesis of 117-phenothiazin-l-one (83), a member of a novel class of heterocyclic o-quinone-imines, by oxidation of 1-hydroxyphenothiazine in an inert solvent under carefully controlled conditions has been reported. A dominant feature of the chemical behaviour of (83) is its tendency to undergo dimerization to give a rather intractable product, identified tentatively as (84). A multi-step synthesis of l-methyl-2-aminophenothiazin-3-one has also been described.  

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Table 1 Basic structures of phenothiazine and related compounds...

Metabolism of phenothiazines and related compounds was the subject of an entire issue of Agressologie ... 

As part of the series Topics in Heterocyclic Chemistry, this volume titled Bioactive Heterocycles II presents comprehensive and up-to-date reviews on selected topics concerning flavonoids and anthocyanins in plants, and heterocycles such as bioactive phenothiazines, phenoxazines, and related compounds. The volume is separated into two sections mainly concentrating on these two topics. 

In the second section of the volume, N-hclerocycles such as phenothiazines, phenoxazines, dihydropyridines, and related compounds are shown also to have interesting biological activity including antitumor activity, vermicide, antibacterial activity, and antischizophrenic activity (i.e. chlorpromazine of the phenothiazine family and its analogs). The activity of phenothiazine and compounds such as phenoxazines and related heterocycles, and also recent bioactive mesoionic heterocycles will be discussed. 

A. L. Green. Ionisation constants and water solubilities of some aminoalkyl phenothiazine tranquillizers and related compounds. /. Pharm. Pharmacol, 19, 10-16 (1967)... 

The unwanted side-effects of drags can be a productive source of leads to new compounds. The evaluation of side-effects for their possible use in therapeutics has made a substantial contribution to our therapeutic arsenal. The various phenothiazine-type tranquillizers, for instance, are derived from the originally undesired sedative side-effect of promethazine, a phenothiazine-type antihistamine. Further incidental observations led to a large family of phenothiazines and related drags (Fig. 5). 

Of the other sedatives and tranquillizers, tetrabenazine and related compounds have properties similar to reserpine, including the ability to reduce the monoamine content of brain and phenothiazine derivatives with tranquillizing actions uncouple oxidative phosphorylation and inhibit ATPase activity to an extent roughly corresponding to their tranquillizing... 

Phenothiazines and related rigid compounds - The antihallucinatory effect of chlorpromazine correlates with serum levels of prolactin, 2 consistent with the DA hypothesis of schizophrenia. No regional site-specificity for limbic areas was found with thioridazine or with clozapine. An excellent correlation between daily clinical dose and the dose-dependent increase in cocaine self-administration in rats was found for seven typical and atypical neuroleptics. Clozapine, however, produced a dose-dependent decrease in cocaine intake. 

The Cadogan reaction refers to the deoxygenation of o-nitrostyrenes 1 or o-nitrostilbenes with trialkyl phosphite or trialkylphosphine and subsequent cyclization of the resulting intermediate nitrene 2 to form indoles 3. The reductive cyclization protocol has also been exploited to prepare a variety of A -containing heterocyclic compounds including carbazoles, indazoles, benzimidazole, benzotriazoles, anthranils, phenazines, phenothiazines, quinolines, and related compounds. 

Cadogan himself further extended the scope of the Cadogan reaction. As early as in 1965, he already prepared carbazoles, indoles, indazoles, thiazoles and related compounds. In 1966, he synthesized phenothiazine (21) and anthranil 23, respectively, employing the reductive cyclization of nitrocompounds by triethyl phosphite. ... 

Finally, Section C of Fig. 17 summarizes some of the important CNS species and related compounds which definitely are not electrochemically active. Neither ACh, GABA, nor any of the amino acids (except tyrosine and glutathione, as mentioned earlier) are electroactive. Many drugs like amphetamine and / -chloroamphetamine are innocuous from the electrochemical viewpoint. As a rule of thumb, any drug having an aromatic hydroxyl, amino or sulfhydryl function, or a phenothiazine-like structure may be electro-oxidizable. However, it is always advisable to check the electrochemistry of any new drug. 

Phenothiazine derivatives and related compounds oxidise rapidly if dissolved. This degradation can be inhibited by the addition of 0.5 % ascorbic acid. 

Phenothiazines (Dibenzo-l 4-thiazines) and Related Compounds.—Further extensive work has appeared on the structure and mode of formation of the green compound that is formed by oxidation of phenothiazine under... 

For the related compounds, phenothiazine and phenoxazine, the reduced form is stable under ambient conditions and oxidation occurs in two one-electron steps. A comparison between the redox behaviour of the two compounds is best made in an antimony trichloride medium where both the radical-cation and the dication levels are stable (Scheme 6.9) [225]. In perchloric acid, phenothiazine shows reversible... 

Tsakovska [194] used methods of molecular modeling to investigate a group of 25 phenothiazines and structurally related compounds. The role of hydrophobicity of modulators and hydrogen-bond acceptor interactions in MDR reversal were revealed. The piperazine moiety with a tertiary nitrogen was identified as the most favorable type of side chain for effective MDR modulators. 

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