The present invention relates to benzazabicyclic carbamates of the formulae I and II below, and the pharmaceutically acceptable salts of such compounds. The compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from Dementia and Alzheimer's disease. The compounds of formula II are novel intermediates used in the synthesis of compounds of formula I. As set forth in detail below, the compounds of formula I and certain of the compounds of formula II are also useful as analgesic agents.
Alzheimer's disease is associated with degeneration of cholinergic neurons in the basal forebrain that play a fundamental role in cognitive functions, including memory. Becker et al., Drug Development Research, 12, 163-195 (1988). As a result of such degeneration, patients suffering from the disease exhibit a marked reduction in acetylcholine synthesis, choline acetyltransferase activity, acetylcholinesterase activity and choline uptake.
It is known that acetylcholinesterase inhibitors are effective in enhancing cholinergic activity and useful in improving the memory of Alzheimer's patients. By inhibiting acetylcholinesterase enzyme, these compounds increase the level of acetylcholine, a neurotransmitter, in the brain and thus enhance memory. Becker et al., supra, report that behavioral changes following cholinesterase inhibition appear to coincide with predicted peak levels of acetylcholine in the brain. They also discuss the efficacy of the three known acetylcholinesterase inhibitors physostigmine, metrifonate, and tetrahydroaminoacridine.
European Patent 0253372 refers to 1,2,3,3a,8,8-ahexahydro -3a,8 (and 1,3a,8) -di (and tri) methylpyrrolo /2,3-b/indoles of the formula ##STR2## wherein R, R.sub.1, X, Z, and m are as defined in such patent, and states that such compounds inhibit acetylcholinesterase are useful as memory enhancing and analgesic agents.
European Patent 0154864 refers to physostigmine derivatives of the formula ##STR3## wherein R is (C.sub.2 -C.sub.20) alkyl, branched alkyl, cycloalkyl or aryl, and states that such compounds inhibit acetylcholinesterase and are useful in the treatment of Alzheimer's disease.
Yu et al., Febs Letters, 234, 1, 127-130, (1988), refer to physostigmine derivatives of the formula ##STR4## wherein R is as defined in such article, and discuss their relative potencies as inhibitors of acetylcholinesterase and butylcholinesterase as compared to the corresponding potency of physostigmine.
Atack et al., J. Pharmacology and Experimental Therapeutics, 249, 1, 194-202 (1989), refer to certain carbamoyl and N(1)-substituted analogs of physostigmine and discuss their relative potency as cholinesterase inhibitors as compared to physostigmine.
Brufani et al., Eur. J. Blochem, 157, 115-120 (1986), refer to physostigmine analogs of the formula ##STR5## wherein R.sup.1 is an alkyl group and R.sup.2 is hydrogen, and state that such compounds possess anticholinesterase activity.
Known cholinesterase inhibitors are useful over a relatively small range of concentrations and exhibit adverse side effects, becoming exremely toxic at concentrations substantially higher than the effective range. Also, the relationship between cholinesterase inhibition and changes in acetylcholine concentrations that follow such inhibition has been shown to be unpredictable, not solely the result of percent cholinesterase inhibition, and strongly affected by the properties of individual drugs. There is therefore a great need for novel cholinesterase inhibitors.