Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-01-14
2000-07-18
MacMillan, Keith D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514326, 514335, 514332, 514358, 514354, 514355, 514356, 514357, A61K 31495, A61K 31455, A61K 3144
Patent
active
060908076
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the use of heterocyclic compounds. Said compounds have valuable therapeutic properties and can be used to treat disorders which respond to dopamine D.sub.3 receptor ligands.
Compounds of the type under discussion here and having physiological activity have been disclosed. Thus, U.S. Pat. No. 4,404,382 describes corresponding imidazole compounds with antiallergic activity.
U.S. Pat. No. 3,362,956 likewise describes imidazole compounds of this type. The latter have adrenolytic and anticonvulsant activity.
DE-A-22 58 033 describes pyrazole compounds with central depressant activity.
DE-A-27 17 415 describes furan, thiophene, oxazole and thiadiazole compounds which can be used to treat hypersensitivity disorders.
Neurous obtain 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.
There is confirmed evidence of the presence of dopamine and its physiological function as neurotransmitter. Cells which respond to dopamine are involved in 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: 164-151, 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. These showed that most dopamine antagonists, such as neuroleptics, have high affinity for D.sub.2 receptors but only low affinity for D.sub.3 receptors.
The prior art compounds described above are such D.sub.2 receptor agonists and antagonists.
It has now been 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 the use of compounds of the formula I: may comprise at least one group which is selected from among O, S, NR.sup.4, CONR.sup.4, NR.sup.4 CO, COO, OCO and a double or triple bond, ##STR1## Ar is phenyl, pyridyl, pyrimidyl or triazinyl, where Ar may have one to four substituents which are, independently of one another, selected from among OR.sup.4, C.sub.1 -C.sub.8 -alkyl, C.sub.2 -C.sub.8 -alkenyl, C.sub.2 -C.sub.8 -alkynyl, halogen, CN, CO.sub.2 R .sup.4, NO.sub.2, SO.sub.2 R.sup.4, SO.sub.3 R.sup.4, NR.sup.4 R.sup.5, SO.sub.2 NR.sup.5 R.sup.5, SR.sup.4, CF.sub.3, CHF.sub.2, a 5- or 6-membered carbocyclic, aromatic or non-aromatic ring and a 5- or 6-membered heterocyclic, aromatic or non-aromatic ring having 1 to 3 hetero atoms which are selected from among O, S and N, where the carbocyclic or the heterocyclic ring is 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, ##STR2## where R.sup.1, R.sup.2 and R.sup.3 are, independently of one another, H, halogen, OR.sup.5, NR.sup.4 R.sup.5.sub.1, SR.sup.4, CF.sub.3, CN, CO.sub.2 R.sup.4 or C.sub.1 -C.sub.8 -alkyl which is unsubstituted or substituted by OH, OC.sub.1 -C.sub.8 -alkyl or halogen, substituted by OH, OC.sub.1 -C.sub.3 -alkyl or halogen; R.sup.4 ; physiologically tolerated acids, which respond to dopamine D.sub.3 receptor antagonists or agonists.
The compounds according to the invention are selective dopamine D.sub.3 receptor ligands which intervene regioselectively in the limbic system. Because of their low affinity for the D.sub.2 receptor, they have fewer side effects than the classical neuroleptics which are D.sub.2 antagonists. The compounds can therefore
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Bach Alfred
Hellendahl Beate
Lansky Annegret
Rendenbach-Muller Beatrice
Teschendorf Hans-Jurgen
BASF - Aktiengesellschaft
MacMillan Keith D.
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