Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-01-14
2000-09-26
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544295, A61K 31505, C07D40314
Patent
active
061242942
DESCRIPTION:
BRIEF SUMMARY
The invention relates to triazole compounds and to the use of such compounds. Said compounds have valuable therapeutic properties and can be used to treat disorders which respond to dopamine D.sub.3 receptor ligands.
Compounds which are of the type under discussion here and have physiological activity have been disclosed. U.S. Pat. Nos. 4,338,453, 4,408,049 and 4,577,020 describe triazole compounds which have antiallergic activity.
Neurons receive their information inter alia via G protein-coupled receptors. There are numerous substances which exert their effect via these receptors. One of them is dopamine.
Confirmed findings on the presence of dopamine and its physiological function as neurotransmitter have been published. Cells which respond to dopamine are connected with the etiology of schizophrenia and Parkinson's disease. These and other disorders are treated with drugs which interact with dopamine receptors.
By 1990, two subtypes of dopamine receptors had been clearly defined pharmacologically, namely D.sub.1 and D.sub.2 receptors.
Sokoloff et al., Nature 1990, 347: 146-151, found a third subtype, namely D.sub.3 receptors. They are expressed mainly in the limbic system. The D.sub.3 receptors differ structurally from the D.sub.1 and D.sub.2 receptors in about half the amino-acid residues.
The effect of neuroleptics has generally been ascribed to their affinity for D.sub.2 receptors. Recent receptor-binding studies have confirmed this. According to these, most dopamine antagonists, like neuroleptics, have high affinity for D.sub.2 receptors but only low affinity for D.sub.3 receptors.
We have now found, surprisingly, that the compounds according to the invention have a high affinity for the dopamine D.sub.3 receptor and only a low affinity for the D.sub.2 receptor. They are thus selective D.sub.3 ligands.
The present invention therefore relates to triazole compounds of the formula I: ##STR1## where A is a straight-chain or branched C.sub.1 -C.sub.18 -alkylene group which may comprise at least one group selected from O, S, NR.sup.3, CONR.sup.3, NR.sup.3 CO, COO, OCO, C.sub.3 -C.sub.6 -cycloalkylene or a double or triple bond, X is a radical of the formula: ##STR2## R.sup.1 is H, CO.sub.2 R.sup.3, NR.sup.3 R.sup.4, OR.sup.4, C.sub.3 -C.sub.6 -cycloalkyl or C.sub.1 -C.sub.8 -alkyl which is unsubstituted or substituted by OH, OC.sub.1 -C.sub.8 -alkyl or halogen; halogen or CN; substituted by OH, OC.sub.1 -C.sub.8 -alkyl, phenyl or halogen; R.sup.3 ; to four substituents which are selected, independently of one another, from OR.sup.4, C.sub.1 -C.sub.8 -alkyl, C.sub.2 -C.sub.6 -alkenyl, C.sub.2 -C.sub.6 -alkynyl, halogen, CN, CO.sub.2 R.sup.3, NO.sub.2, SO.sub.2 R.sup.3, SO.sub.3 R.sup.3, NR.sup.3 R.sup.4, SO.sub.2 NR.sup.3 R.sup.4, SR.sup.3, CF.sub.3, CHF.sub.2, a 5- or 6-membered carbocyclic aromatic or nonaromatic ring and a 5- or 6-membered heterocyclic aromatic or nonaromatic ring having 1 to 4 hetero atoms selected from O, S and N, where the carbocyclic or heterocyclic ring may be unsubstituted or substituted by C.sub.1 -C.sub.8 -alkyl, halogen, OC.sub.1 -C.sub.8 -alkyl, OH, NO.sub.2 or CF.sub.3 and where Ar may also be fused to a carbocyclic or heterocyclic ring of the type defined above, and the salts thereof with physiologically tolerated acids.
The compounds according to the invention are selective dopamine D.sub.3 receptor ligands which intervene regioselectively in the limbic system and, because of their low affinity for the D.sub.2 receptor, have fewer side effects than classical neuroleptics, which are D.sub.2 receptor antagonists. The compounds can therefore be used to treat disorders which respond to dopamine D.sub.3 receptor antagonists or agonists, eg. for treating disorders of the central nervous system, in particular schizophrenia, depression, neuroses and psychoses. They can additionally be used to treat sleep disorders and nausea and as antihistamines.
Within the scope of the present invention, the following terms have the meanings indicated below:
Alkyl (also in radicals such as alkox
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Bialojan Siegfried
Drescher Karla
Hellendahl Beate
Lansky Annegret
Munschauer Rainer
BASF - Aktiengesellschaft
Morris Patricia L.
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