Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-04-16
1999-06-29
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514322, 514323, 546197, 546198, 546199, 546201, A61K 31445, C07D40106, C07D40112
Patent
active
059169028
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to the compound of the formula I, below, and pharmaceutically acceptable salts and pro drugs thereof. More particularly, it relates to processes and intermediates for use in the preparation of the compound of formula I.
The compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from dementia and Alzheimer's disease.
The compound of formula I is disclosed in co-pending U.S. patent application Ser. No. 08/127,847 (assigned to the Assignee of this application), incorporated herein by reference.
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 the acetylcholinesterase enzyme, these compounds increase the level of the neurotransmitter acetylcholine 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.
All documents cited herein, including the foregoing, are incorporated herein in their entireties.
SUMMARY OF THE INVENTION
The present invention relates to processes and intermediates, and processes for the preparation of said intermediates, for the preparation of the compound of the formula ##STR3##
More particularly, the invention relates to a process for the preparation of the compound of formula I which comprises ##STR4## wherein R.sup.3 is benzyl or R.sup.4, wherein R.sup.4 is selected from R.sup.5 --C(.dbd.O)--, R.sup.5 SO.sub.2 -- and R.sup.5 OC(.dbd.O)-- and R.sup.5 is (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl or aryl(C.sub.1 -C.sub.6)alkyl; with hydroxylamine to form the compound of formula ##STR5## wherein R.sup.3 is as defined above; b) treating the compound of formula VI with an acylating agent selected from the group comprising acyl or aroyl anhydrides, halides and esters; or a sulfonating agent selected from the group comprising alkyl, aryl or aralkyl sulfonyl halides and anhydrides, and halides of groups of the formula R.sup.5 OC(.dbd.O)-- to form the compound of formula ##STR6## wherein R.sup.3 and R.sup.4 are as defined above; c) treating the compound of formula VII with a base at an elevated temperature, to form ##STR7## the compound of formula I; or ii) when R.sup.3 is not benzyl, the compound of the formula ##STR8##
2) treating the compound of formula VIII, wherein R.sup.3 is not benzyl with an aqueous mineral acid at an elevated temperature and then with a base to form the compound of formula ##STR9##
3) treating the compound of formula IX with a benzylating agent in the presence of a base to form the compound of formula I. A preferred benzylating agent is a benzyl halide, preferably benzyl bromide, and a preferred base is triethanolamine
This invention also relates to compounds of the formula ##STR10## R.sup.1 is H and R.sup.2 is OH or OR.sup.4 wherein R.sup.4 is 4R.sup.5 C(.dbd.O), R.sup.5 OC(.dbd.O) or R.sup.5 SO.sub.2 wherein R.sup.5 is (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl or (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl; or R.sup.1 and R.sup.2 together form a single bond, R.sup.3 is R.sup.4 or benzyl with the proviso that when R.sup.1 and R.sup.2 together form a single bond, R.sup.3 is not benzyl. These compounds are useful as intermediates in the synthesis of compounds of the formula I.
More specifically, this invent
REFERENCES:
patent: 5532240 (1996-07-01), Nakao et al.
patent: 5538984 (1996-07-01), Villalobos et al.
McOmie "Protective groups in organic chemistry" Plen. Press, p. 109-120 1973.
DeVries Keith M.
Villalobos Anabella
Chang Ceila
Ginsburg Paul H.
Ling Lorraine B.
Pfizer Inc.
Richardson Peter C.
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