Chemistry of the phenoxathiins V. Correlation of the crystal and molecular structure with pharmacologic activity associated with 7‐ and 8‐chloro‐l‐azaphenoxathiin

Abstract

The crystal and molecular structure of the 7‐ and 8‐chloro analogs of the 1‐azaphenoxathiin system are described. In contrast to previous compounds possessing antipsychotic type activity, the title compounds are both nearly planar, and demonstrate significant substituent location sensitivity, with the 7‐chloro analog exhibiting significant biologic activity while the 8‐chloro isomer is nearly devoid of activity. The relationship of these compounds to the isosterically related phenothiazines in terms of design and molecular geometry considerations is also described.

First Synthesis of 3-Mercapto-2(1H)-pyridinone, a Simple Disubstituted Pyridine Useful for Synthesis of the 4-Azaphenoxathiine Ring System and Its Novel Diazaphenoxathiine Analogs: 1,6-Diazaphenoxathiine and 2,6-Diazaphenoxathiine1

“…6a The absence of 13 C data on the parent 4-azaphenoxathiine isomer is a significant gap in the literature, however, and limits the confidence with which the NMR spectra of related phenoxathiines can be assigned. It was therefore important to attempt the assignment of the 13 C NMR spectra of 4-azaphenoxathiine (10), 1,6-diazaphenoxathiine ( 12), 2,6-diazaphenoxathiine (15), and 2,6-diazaphenoxathiine 2-oxide (14) (see Table 1).…”

“…Some unsubstituted 1-azaphenoxathiines have shown central nervous system depressant activity, 3,4 and the influence of azasubstitution in the benzenoid rings on the shape and biological activity of these systems has encouraged the synthesis of several other monoazaphenoxathiines [5][6][7][8] and diazaphenoxathiines. 9 It transpires that azaphenoxathiines are essentially planar, 10 in contrast to the phenoxathiine parent ring system. 11 Despite the synthesis of several additional members of this interesting group of ring systems in recent years, until now there are no reports of the parent 4-azaphenoxathiine (10), 1,6-diazaphenoxathiine (12), or 2,6diazaphenoxathiine (15) ring systems.…”

“…9 It transpires that azaphenoxathiines are essentially planar, 10 in contrast to the phenoxathiine parent ring system. 11 Despite the synthesis of several additional members of this interesting group of ring systems in recent years, until now there are no reports of the parent 4-azaphenoxathiine (10), 1,6-diazaphenoxathiine (12), or 2,6diazaphenoxathiine (15) ring systems. One substituted derivative of 4-azaphenoxathiine 6 has been obtained via a complex route which is not general.…”

Librational effects on carbon-13 N.M.R. spin-lattice relaxation times of tricyclic condensed molecules

“…The correlation function pertinent to the internal motion appearing in equation (8) can be evaluated from…”

“…In this way we wish to contribute to the understanding of the internal conformational flexibility of I (where X and Y are bivalent atoms and groups, e.g. : O, S, Se, Te, NH, CH2, SO2) ; this problem is particularly relevant to some pharmacologically active compounds whose preferred conformation has been found to be folded along the X-Y axis, as shown in the figure, in the solid as well as in the fluid solution state [7,8].…”