Triazole compounds and the use thereof as dopamine-D3 -ligands

Details Triazole compounds and the use thereof as dopamine-D3 -ligands Triazole compounds and the use thereof as dopamine-D3 -ligands

1999-12-28

2002-10-29

Rao, Deepak R. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252110, C514S252190, C514S253050, C514S253090, C514S242000, C514S318000, C514S326000, C514S333000, C514S340000, C544S182000, C544S198000, C544S212000, C544S328000, C544S331000, C544S363000, C544S364000, C544S366000, C544S357000, C546S194000, C546S210000

Reexamination Certificate

active

06472392

ABSTRACT:

The present invention relates to triazole compounds and to the use of such compounds. The compounds mentioned have valuable therapeutic properties and can be used for treating diseases which respond to dopamine D
3
receptor ligands.
Compounds of this type having 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 or antipsychotic activity. DE-A 44 25 144 and WO 97/25324 describe triazole compounds which respond to dopamine D
3
receptor ligands. Compounds of the same structural type, however with other heterocycles in place of the triazole ring are disclosed in DE-A-44 25 146, DE-A-44 25 143 and DE 44 25 145.
Neurons obtain their information by way of G protein-coupled receptors, inter alia. A large number of substances exert their effect by way of these receptors. One of these substances is dopamine.
It is known with certainty that dopamine is present and that it has a physiological function as a neurotransmitter. Cells responding to dopamine are connected with the etiology of schizophrenia and Parkinson's disease. These and other diseases are treated with drugs which interact with the dopamine receptors.
Prior to 1990, two dopamine receptor subtypes were clearly defined pharmacologically, ie. the D
1
and D
2
receptors.
More recently, a third subtype has been found, ie. the D
3
receptor, which appears to mediate some of the effects of the antipsychotic drugs. (J. C. Schwartz et al., The Dopamine D
3
Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144)
D
3
receptors are principally expressed in the limbic system. It is therefore assumed that a selective D
3
antagonist would probably have the antipsychotic properties of the D
2
antagonists but would not have their neurological side effects. (P. Solokoff et al., Localization and Function of the D
3
Dopamine Receptor,
Arzneim. Forsch./Drug Res.
42(1), 224 (1992); P. Solokoff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D
3
) as a Target for Neuroleptics,
Nature,
347, 146 (1990)).
Surprisingly, it has now been found that certain triazole compounds exhibit a high affinity for the dopamine D
3
receptor and a low affinity for the D
2
receptor. These compounds are therefore selective D
3
ligands.
The present invention relates, therefore, to compounds of the formula I:
where
Ar
1
is phenyl, naphthyl or a 5- or 6-membered heterocyclic aromatic ring having from 1, 2, 3 or heteroatoms which are independently selected from O, S and N, where Ar
1
may have 1, 2, 3 or 4 substituents which are selected, independently of each other, from C
1
-C
6
-alkyl, which may be substituted by OH, OC
1
-C
6
-alkyl, halogen or phenyl, C
1
-C
6
-alkoxy, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, C
3
-C
6
-cycloalkyl, halogen, CN, COOR
2
, NR
2
R
2
, NO
2
, SO
2
R
2
, SO
2
NR
2
R
2
, or phenyl, which may be substituted by C
1
-C
6
-alkyl, OC
1
-C
6
-alkyl, NR
2
R
2
, CN, CF
3
, CHF
2
, or halogen, and where the heterocyclic, aromatic ring mentioned may be fused to a phenyl ring;
A is straight-chain or branched C
4
-C
10
-alkylene or straight-chain or branched C
3
-C
10
-alkylene which comprises at least one group Z which is selected from O, S, NR
2
, CONR
2
, COO, CO, or a double or triple bond,
B is a radical of the formula:
or, if Ar
1
represents the 5- or 6-membered, heterocyclic or aromatic ring which may be substituted as indicated, B may also be a radical of the formulae
Ar
2
is phenyl, pyridyl, pyrimidinyl or triazinyl, where Ar
2
may have from 1 to 4 substituents which are selected, independently of each other, from OR
2
, C
1
-C
6
alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, C
l
-C
6
-alkoxy-C
l
-C
6
-alkyl, halogen-C
1
-C
6
-alkyl, halogen-C
1
-C
6
-alkoxy, halogen, CN, NO
2
, SO
2
R
2
, NR
2
R
2
, SO
2
NR
2
R
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 or 2 heteroatoms which are selected from O, S and N, where the carbocyclic or heterocyclic ring may be substituted by C
l
-C
6
-alkyl, phenyl, phenoxy, halogen, OC
1
-C
6
-alkyl, OH, NO
2
or CF
3
and where Ar
2
may be fused to a carbocyclic or heterocyclic ring of the above-defined nature,
R
1
is H, C
3
-C
6
-cycloalkyl or C
1
-C
6
-alkyl which may be substituted by OH, OC
1
-C
6
-alkyl or phenyl;
the radicals R
2
, which can be identical or different, are H or C
1
-C
6
-alkyl, which may be substituted by OH, OC
1
-C
6
-alkyl or phenyl;
and their salts with physiologically tolerated acids.
The novel compounds are selective dopamine D
3
receptor ligands which act in a regioselective manner in a limbic system and which, due to their low affinity for the D
2
receptor, have fewer side effects than the classic neuroleptics, which are D
2
receptor antagonists. The compounds can therefore be used for treating diseases which respond to dopamine D
3
receptor antagonists or dopamine D
3
receptor agonists, eg. for treating diseases of the central nervous system, in particular schizophrenia, depressions, neuroses, psychoses, parkinson and anxiety.
Within the context of the present invention, the following expressions have the meanings given in conjunction with them: Alkyl (also in radicals such as alkoxy, alkylamino, etc.) is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms and, in particular, from 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of each other, from OH, OC
1
-C
6
-alkyl, halogen or phenyl.
Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, etc.
Cycloalkyl is, in particular, C
3
-C
6
-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Alkylene radicals are straight-chain or branched. If A does not have any group Z, A then comprises from 4 to 10 carbon atoms, preferably from 4 to 8 carbon atoms. The chain between the triazole nucleus and group B then has at least 4 carbon atoms. If A has at least one of said Z groups, A then comprises from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms.
If the alkylene groups comprise at least one of the Z groups, these may either be arranged in the alkylene chain at an arbitrary site or in position 1 or 2 of group A (seen from the Ar
1
radical). The radicals CONR
2
and Coo are preferably arranged such that the carbonyl group is facing the triazole ring. Particularly preferred are compounds of the formula I in which A is —Z—C
3
-C
6
-alkylene, in particular —Z—CH
2
CH
2
CH
2
—, —Z—CH
2
CH
2
CH
2
CH
2
—, —Z—CH
2
CH=CHCH
2
—, —Z—CH
2
C(CH
3
)=CHCH
2
—, —Z—CH
2
C(=CH
2
)CH
2
—, —Z—CH
2
CH(CH
3
)CH
2
— or a linear —Z—C
7
-C
10
-alkylene radical, with Z being attached to the triazole ring. Z is preferably CH
2
, O and in particular S. Further preferably is A —(CH
2
)
4
—, —(CH
2
)
5
—, —CH
2
CH
2
CH=CHCH
2
—, —CH
2
CH
2
C(CH
3
)═CHCH
2
—, —CH
2
C(═CH
2
)CH
2
—, or —CH
2
CH
2
CH(CH
3
)CH
2
—.
Halogen is F, Cl, Br or I.
Haloalkyl can comprise one or more, in particular 1, 2, 3 or 4, halogen atoms which can be located on one or more C atoms, preferably in the &agr;- or &ohgr;-position. CF
3
, CHF
2
, CF
2
Cl or CH
2
F are particularly preferred.
Acyl is preferably HCO or C
1
-C
6
-alkyl-CO, in particular acetyl. When Ar
1
is substituted, the substituent can also be located on the nitrogen heteroatom.
Preferably, Ar
1
is
where
R
3
to R
6
are H or the abovementioned substituents of the radical Ar
1
,
R
7
is H, C
1
-C
6
-alkyl or phenyl, and
X is N or CH. If the phenyl radical is substituted, the substituents are preferably in the m position or the p position.
Particularly preferably, Ar
1
is
where R
3
and R
4
have the abovementioned meanings. The phenyl, pyrazinyl and pyrrole radicals which are indicated are particularly preferred.
The radicals R
3
to R
6
are preferably H, C
1
-C
6
-alkyl, OR
2
, CN, phenyl which may be substituted by

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