Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-08-30
2000-09-12
Lambkin, Deborah C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514326, 514299, 546133, 546137, 546210, 546112, A61K 3144, A61K 31445, C07D45302, C07D40100, C07D22102
Patent
active
061178837
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to therapeutically active heterocyclic compounds having surprising potency at a muscarinic receptor. The novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals.
Due to the generally improved health situation in the western world, elderly-related diseases are much more common now than in the past and are likely to be even more common in the future.
One of the elderly-related symptoms is a reduction of the cognitive functions. This symptom is especially pronounced in the pathophysiological disease known as Alzheimer's disease. This disease is combined with, and also most likely caused by, an up to 90% degeneration of the muscarinic cholinergic neurons in nucleus basalis, which is part of substantia innominata. These neurons project to the prefrontal cortex and hippocampus and have a general stimulatory effect on the cognitive functions of the forebrain as well as of hippocampus, namely learning, association, consolidation, and recognition.
It is a characteristic of Alzheimer's disease that although the cholinergic neurons degenerate, the postsynaptic muscarinic receptors in the forebrain and hippocampus still exist. Therefore, muscarinic cholinergic agonists are useful in the treatment of Alzheimer's disease, in halting its progression, and in improving the cognitive functions of elderly people.
Compounds active at a muscarinic cholinergic receptor are also useful analgesic agents and therefore are useful in the treatment of severely painful conditions.
Furthermore, muscarinic cholinergic receptor active compounds are useful in the treatment of glaucoma, psychosis, anxiety, mania, bipolar disorder, schizophrenia or schizophreniform conditions, depression, sleeping disorders, epilepsy, cerebral ischemia, and gastrointestinal motility disorders.
Therefore, new compounds having muscarinic cholinergic activity are desired. Some muscarinic cholinergic receptor active compounds are associated with side effects attributed to undesired modulation of the muscarinic cholinergic receptors, for example, such undesired modulation may cause excessive salivation and gastrointestinal upset. Thus, the most desired muscarinic cholinergic compounds shall have high potency and at the same time a favorable side effect profile, including a low incidence of excessive salivation.
The presently claimed compounds having a cyclopropanemethoxy substituent are surprisingly potent as M.sub.1 agonists and provide a favorable side effect profile.
This invention provides compounds of the formula I: ##STR1## wherein R is selected from the group consisting of hydrogen, --CN, halogen, --CF.sub.3 and R.sup.4 ; C.sub.2-6 -alkenyl and C.sub.2-6 -alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), --CF.sub.3, and --CN; systems: ##STR2## R.sup.1 and R.sup.2 independently are selected from the group consisting of hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, and C.sub.1-5 -alkyl substituted with one or more independently selected from the group consisting of --OH, --COR.sup.6', CH.sub.2 --OH, halogen, --NH.sub.2, carboxy, unsubstituted phenyl and phenyl substituted at any position with R.sup.6' ; -alkyl, C.sub.2-5 -alkenyl and C.sub.2-5 -alkynyl;
It is an object of the invention to provide new muscarinic cholinergic compounds having surprising potency as M-1 receptor active compounds and a favorable side effect profile.
It is to be understood that the invention extends to each of the stereoisomeric forms of the compounds of the present invention as well as the pure diastereomeric, pure enatiomeric, and racemic forms of the compounds of this invention.
As used herein the term "treating" includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established or alleviation of the characteristic symptoms of such condition.
As used herein the phrase "inte
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Merritt Leander
Reel Jon K
Simon Richard L
Whitesitt Celia A
Eli Lilly and Company
Lambkin Deborah C.
Palmberg Arleen
Stemerick David M.
Vorndran-Jones MaCharri
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