Synthesis of 7-(Dialkylaminoalkyl)-benzo [c] phenothiazines; The Metalation of 7H-Benzo [c] phenothiazine With n-Butyllithium

Introduction: Phenothiazine is one of the more widely investigated heterocyclic molecules known to modern chemistry. The founding of the synthetic dye industry in the latter part of the nineteenth century stimulated many new fields of organic research, one of which was phenothiazine chemistry. Bernthsen, known as father of phenothiazine chemistry, first synthesized (1) this compound in 1883, after suspecting its presence in the nucleus of the methylene blue dyes.

Since that time phenothiazine and its derivatives have found uses as antioxidants (2), antihistamines (3), antiemetics (4), and in the treatment of Parkinson's disease (5). During the past decade, considerable attention has been given to N-(dialkylaminoalkyl)-phenothiazine types because of their excellent effect in suppressing nausea (4) and in the treatment of neruopsychiatric disorders (6). More recently, the tranquilizing activity of certain N-(dialkylaminoalkyl)-phenothiazine types has been reported (7), Thus, the pharmacological usefulness of phenothiazine derivatives is well-established.

On the other hand, the known chemistry of the benzophenothiazines is quite limited. Vast opportunity exists for chemotherapeutic investigations in this area, and only recently some penetration into this field of endeavor was begun. In 1942, it was (8) demonstrated that tumor growth inhibition occurred with some simple benzophenothiazine types. Talukdar and Shirley (9) recently prepared a series of 12-(dialkylaminoalkyl)-benzo [a] phenothiazines for pharmacological evaluation, but the results of these tests are not yet available.

In view of such a wide spectrum of pharmacological application enjoyed by phenothiazine and its derivatives, and the opportunity for chemotherapeutic investigation in the field of benzophenothiazine chemistry, it is felt that benzophenothizines structurally related to some of the more useful phenothiazine types should be synthesized and pharmacologically evaluated. This research is primarily concerned with the preparation of 7-(dialkylaminoalkyl)-benzo [c] phenothiazines, compounds similar in structure to the therapeutically useful phenothiazine types.

In connection with the synthesis of these N-alkylated benzophenothiazines, there was considerable interest in finding new and better methods of introducing substituents into the lesser accessible positions of the benzophenothiazine nucleus. In an effort to do this, a study of the metalation of 7H-benzo [c] phenothiazine with n-butyllithium was undertaken.

The compounds prepared in this investigation are currently being tested by the Eli Lilly Company of Indianapolis, Indiana, for central nervous system effects and by the National Cancer Institute for anti-cancer activity. It is hoped that the results of this research will in some way benefit the extensive program now being conducted for the development of new and more useful drugs.