Antianxiety drugs, also known as anxiolytic drugs or tranquilizers, are increasingly important psychotropic drugs. They include the benzodiazepines, such as diazepam, chlordiazepoxide, gidazepam, oxazepam, phenazepam, lorazepam, and the like. These benzodiazepines have been the most widely used drugs for the treatment of anxiety. Other antianxiety drugs include, buspirone, gepirone, ipsapirone, and other drugs with high affinity and selectivity for 5HT1.sub.a receptor sites. See for example, Abou-Gharbia et al., J. Med. Chem., 32, 1024 (1989).
These agents have been very effective but there has been increasing concern about the disadvantages associated with benzodiazepine therapy. The spectrum of their pharmacological activity, in addition to anxiolytic activity, includes sedative, anticonvulsant, miorelaxant, and amnestic effects, which are often considered both unnecessary and undesirable in the treatment of pathological anxiety. Thus a substantial need exists for nontoxic, highly active, selectively anxiolytic drugs without sedative, muscle relaxant and amnestic activities, which can be used for the treatment of anxiety. The present invention is directed to addressing this need.
A number of compounds having 1,2,3,4-tetrahydropyrrolo-[1,2-a]-pyrazine heterocycle have been reported. For example, nonsubstituted 1,2,3,4-tetrahydropyrrolo-[1,2-a]-pyrazine is described by A. Skoldinov et al. (U.S. Pat. No. 4,230,856 issued Oct. 28, 1980; USSR Patent No. 798,104 published Jan. 25, 1981). This compound is a precursor in the synthesis of octahydropyrrolo-[1,2-a]-pyrazine, which is useful for the synthesis of physiologically active drugs. 1- and 1,2-substituted 1,2,3,4-tetrahydropyrrolo-[1,2-a]-pyrazine derivatives, having antidepressant activity, are described by I. Jirkovsky (U.S. Pat. No. 4,188,389 issued Feb. 12, 1980). 1-substituted 1,2,3,4-tetrahydropyrrolo-[1,2-a]-pyrazines, having hypotensive activity, are described by V. Peresada et al., Khim-Farm. Zh., 21(9), 1054 (1987). 1-substituted 1,2,3,4-tetrahydropyrrolo-[1,2-a]-pyrazines, possessing coronary-dilating activity, are described by V. Peresada et al., Khim-Farm. Zh., 22(10), 1193 (1988).