Syntheses of (.+-.)-2-((inden-7-yloxy)methyl)morpholine hydrochloride (YM-08054, indeloxazine hydrochloride) and its derivatives with potential cerebral-activating and antidepressive properties.

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Abstract
The synthesis of (.+-.)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride (7 .cntdot. HCl, YM-08054, indeloxazine hydrochloride) and its optical resolution into levo- and dextro-isomers were investigated. A practical synthetic method for 7 .cntdot. HCl was established by employing preferential crystallization from an equilibrium mixture of 7 .cntdot. HCl and its tautomer, (.+-.)-2-[(inden-4-yloxy)methyl]morpholine hydrochloride (6 .cntdot. HCl), in the presence of a catalytic amount of base in MeOH. It was found that 7 .cntdot. HCl and its levo-rotatory isomer ((-)-7 .cntdot. HCl) showed not only strong antidepressive activities, but also potent cerebral-activating properties. The syntheses and pharmacological activities of related compounds are also discussed briefly.