Heterocyclic compounds

Details Heterocyclic compounds Heterocyclic compounds

1999-05-10

2000-05-30

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548135, A61K41712, C07D 3141

Patent

active

06069159&

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to therapeutically active heterocyclic compounds having surprising potency and favorable side effect profile. 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 are surprisingly potent and most preferredly provide a favorable side effect profile. Studies of compounds claimed herein suggest that certain compounds will be highly desired muscarinic receptor active compounds which can be particularly useful pharmaceutically active compounds.
This invention provides compounds of the formula I: ##STR1## W is S or O; R.sup.8 is selected from the group consisting of hydrogen and C.sub.1 -C.sub.4 alkyl; optionally substituted with one or more independently selected from the group consisting of halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2 ; --OH, --COR.sup.6', CH.sub.2 --OH, and --NH.sub.2 ; systems: ##STR2## or G is optionally substituted C.sub.3 -C.sub.8 cycloalkyl wherein the cycloalkyl substituents are selected from R.sup.1 and R.sup.2 ; or optionally substituted C.sub.1-6 -alkyl wherein the substitution is --NR.sup.6 R.sup.7 ; hydrogen and C.sub.1-6 -alkyl; or R.sup.6 and R.sup.7 together with the nitrogen atom optionally form a 4- to 6-member ring; 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, ##STR3## and phenyl; R.sup.9 and R.sup.9' are each independently selected from the group consisting of hydrogen, halogen, C.sub.1-4 -alkoxy, C.sub.1-4 -alkyl, --CN, --OCF.sub.3, --CONH.sub.2 and --CSNH.sub.2 ; -alkyl, C.sub.2-5 -alkenyl and C.sub.2-5 -alkynyl;
Preferred compounds are those wherein R.sup.10' is propargyl.
The present inventi

REFERENCES:
patent: 5821371 (1998-10-01), Alt et al.

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