Heterocyclic compounds and their use

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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Details

514342, 514334, 5462687, 5462694, 546257, A61K 3144, C07D41304

Patent

active

057734526

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to therapeutically active azacyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds.
The novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer's disease.
Due to the in general 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, a 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, then the postsynaptic muscarinic receptors in the forebrain and hippocampus still exist. Therefore muscarinic cholinergic agonists are useful in the treatment of Alzheimer's disease and in improving the cognitive functions of elderly people.
It is well known that arecoline (methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate) is such a cholinergic agonist.
Arecoline however has a very short biological half life and a small separation between central and peripheral muscarinic effects. Furthermore arecoline is a rather toxic compound.
EP-A-0307142 discloses a class of thiadiazoles, substituted on one of the ring carbon atoms with a non-aromatic azacyclic or azabicyclic ring system, and substituted on the other ring carbon atom with a substituent of low lipophilicity, or a hydrocarbon substituent, which are muscarinic agonists and therefore useful in the treatment of neurological and mental illnesses and severe painful conditions.
It is an object of the invention to provide new muscarinic cholinergic compounds.
The novel compounds of the invention are heterocyclic compounds having the formula I ##STR2## wherein
Z.sup.1 is oxygen or sulphur;
R is hydrogen, halogen, amino, --NHCO--R.sup.2, C.sub.3-7 -cycloalkyl, C.sub.4-10 -(cycloalkylalkyl), --Z.sup.2 --C.sub.3-7 -cycloalkyl optionally substituted with C.sub.1-6 -alkyl, --Z.sup.2 --C.sub.4-10 -(cycloalkylalkyl), --Z.sup.2 --C.sub.4-10 -(cycloalkenylalkyl), --Z.sup.2 --C.sub.4-10 -(methylenecycloalkylalkyl), --NH--R.sup.2, --NR.sup.2 R.sup.3, --NH--OR.sup.2, phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphtyl, indenyl, X, R.sup.2, --Z.sup.2 R.sup.2, --SOR.sup.2, --SO.sub.2 R.sup.2, --Z.sup.2 --R.sup.2 --Z.sup.3 --R.sup.3, --Z.sup.2 --R.sup.2 --Z.sup.3 --R.sup.3 --Z.sup.4 --R.sup.4, --Z.sup.2 --R.sup.2 CO--R.sup.3, --Z.sup.2 --R.sup.2 --CO.sub.2 --R.sup.3, --Z.sup.2 --R.sup.2 --O.sub.2 --R.sup.3, --Z.sup.2 --R.sup.2 CONHR.sup.3, --Z.sup.2 --R.sup.2 --NHCOR.sup.3, --Z.sup.2 --R.sup.2 --X, --Z.sup.2 --R.sup.2 --Z.sup.3 --X, wherein Z.sup.2, Z.sup.3 and Z.sup.4 independently are oxygen or sulphur, and R.sup.2, R.sup.3 and R.sup.4 independently are straight or branched C.sub.1-15 -alkyl, straight or branched C.sub.2-15 -alkenyl, straight or branched C.sub.2-15 -alkynyl, each of which is optionally substituted with halogen(s), --OH, --CN, --CF.sub.3, --SH, --COOH, --NH--R.sup.2, --NR.sup.2 R.sup.3, C.sub.1-6 -alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two halogen, --CN, C.sub.1-4 -alkyl or C.sub.1-4 -alkoxy, and X is a 5 or 6 membered heterocyclic group containing one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched C.sub.1-6 -alkyl, phenyl, benzyl o

REFERENCES:
patent: 5041455 (1991-08-01), Sauerberg et al.
patent: 5043345 (1991-08-01), Sauerberg et al.
patent: 5328923 (1994-07-01), Sauerberg et al.
patent: 5328924 (1994-07-01), Sauerberg et al.

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