In the chemistry of phenothiazines

Bodea, C., Silberg, I., Recent Advances in the Chemistry of Phenothiazines, 9, 321. 

Bodea, C., Silberg, L, Recent Advances in the Chemistry of Phenothiazines, 9, 321. Bohle, M., Liebscher, I., Ring Contraction of Heterocycles by Sulfur Extrusion,... 

The first synthesis of phenothiazine was reported by Bernthsen about 80 years ago. In the evolution of the chemistry of this heterocycle, three periods can be discerned. First, phenothiazine was of interest owing to its quinonoid derivatives—an important chapter in sulfur dye chemistry. Research work in the field of phenothiazine was then stimulated by the discovery of the anthelmintic action of unsubstituted and of some C -substituted phenothiazines. During the last two decades, the exceptional pharmacological properties of some A-substituted phenothiazines, e.g., the antihistaminic activity of promethazine, 10-(2-dimethylamino-l-propyl)phenothiazine, and particularly the psychotherapeutic action of chlorpromazine, 2-chloro-10-(3-dimethylamino-1 -propyl )phenothiazine, focused interest mainly on the synthesis and testing of a great number of compounds of this type. The phenothiazine drugs now play a very important part in chemotherapy. 

Some substituted o-quinones react with mercaptoamines to give I-phenothiazi-nones but others (including o-benzoquinone) give more complex products [2635, 3179, 3332]. Cyclic 1,3-diketones (in their tautomeric form) react with a 2-mercaptoaniline to give phenothiazine-like compounds [3285]. The chemistry of phenothiazines has been reviewed [B-44, 3332]. o-Mercaptoaniline is annulated by heating with a hydroxycyclopentadienone [2635]. 

The authors are very much indebted to Professor A. R. Katritzky for his valuable advice and to Mr. Dan Porumb for his contributions to the preparation of the manuscript. loan A. Silberg gratefully acknowledges the enthusiastic support of his research group in carrying on investigations in the field of phenothiazine chemistry. 

Recent progress in the chemistry of 2,1-benzothiazines 08PHC1. Retrosynthetic approaches to the synthesis of phenothiazines 06AHC(90)205. 

Further chemical modification of the phenylpiperidine moiety has proven unusually fruitful in producing medicinal agents that affect the central nervous system. First, a series of compounds loosely related to the reversed meperidines produced several drugs with important antipsychotic activity. Further discussion of this pharmacologic activity, often referred to as major tranquilizer activity, will be found in the section on phenothiazines. The group led by Janssen took advantage of the chemistry of the... 

Computational and combinatorial chemistry methodology helped to create a highly selective phenothiazine derivative which can serve as a novel lead compound for further development in the field of COX-2 inhibitors (Dannhardt and Kiefer, 2001). 

From the very beginning of the phenothiazine chemistry, its capacity to give rise to different oxidation products, now explained in terms of a suecessive electron loss, was realized. The first systematic study on these topics was by Kehrmann, in the first decade of the present century. He suceeeded in explaining the observed phenomena, and it has been proved by recent work that most of his statements are essentially correct. A second stage was marked by Michaelis s work, which stressed the remarkable stability of the semiquinonoid forms obtained both by oxidation of phenothiazines and by reduction of quinoneiminoid phenothiazine dyestuffs. The development of electron spin resonance (ESR) spectroscopy allowed the direet investigation of the radical species, and marked the beginning of a third era in the study of redox processes in the phenothiazine class. 

The ninth volume of Advances in Heterocyclic Chemistry includes surveys of the chemistry of the following groups of heterocyclic compounds 1,2,5-thiadiazoles (L. M. Weinstock and P. I. Pollack) 1,3,4-thiadiazoles (J. Sandstrom) pyridazines (M. Ti ler and B. Stanovnik) Reissert compounds (F. D. Popp) phenothiazines (C. Bodea and I. Silberg) and pyrrolopyridines (R. E. Willette). 

It is now more than 30 years since the first monocyclic 1,4-thiazine was described nevertheless, the chemistry of such compounds is still relatively undeveloped. The 1,4-thiazine ring is of importance in nature where, in fusion with the benzene ring, it is found in the trichochrome pigments. It is also a structural feature of the phenothiazines, synthetic compounds that are of considerable medicinal value. Furthermore, 1,4-thiazines are of in-... 

Knowledge of the chemistry of local anaesthetics also helps in finding possible substitutes, e.g., the replacement of an ester by an amide agent which neither cross-reacts, nor is likely to cause allergy by itself. Many other compounds have local anaesthetic properties, and may be thought of as potential alternatives, e.g., certain phenothiazine antihistamines and propranolol (the jS-adrenoceptor blocker). 

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