Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-13
2002-06-11
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S366000, C544S121000, C544S295000, C544S212000, C514S236200, C514S252110, C514S252190, C514S245000
Reexamination Certificate
active
06403593
ABSTRACT:
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
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
1
and D
2
receptors.
Sokoloff et al., Nature 1990, 347: 146-151, found a third subtype, namely D
3
receptors. They are expressed mainly in the limbic system. The D
3
receptors differ structurally from the D
1
and D
2
receptors in about half the amino-acid residues.
The effect of neuroleptics has generally been ascribed to their affinity for D
2
receptors. Recent receptor-binding studies have confirmed this. According to these, most dopamine antagonists, like neuroleptics, have high affinity for D
2
receptors but only low affinity for D
3
receptors.
We have now found, surprisingly, that the compounds according to the invention have a high affinity for the dopamine D
3
receptor and only a low affinity for the D
2
receptor. They are thus selective D
3
ligands.
The present invention therefore relates to triazole compounds of the formula I:
where
A is a straight-chain or branched C
1
-C
18
-alkylene group which may comprise at least one group selected from O, S, NR
3
, CONR
3
, NR
3
CO, COO, OCO, C
3
-C
6
-cycloalkylene or a double or triple bond,
X is a radical of the formula:
R
1
is H, CO
2
R
3
, NR
3
R
4
, OR
4
, C
3
-C
6
-cycloalkyl or C
1
-C
8
-alkyl which is unsubstituted or substituted by OH, OC
1
-C
8
-alkyl or halogen;
R
2
has the meanings indicated for R
1
or is CF
3
, SR
3
, halogen or CN;
R
3
is H or C
1
-C
8
-alkyl which is unsubstituted or substituted by OH, OC
1
-C
8
-alkyl, phenyl or halogen;
R
4
has the meanings indicated for R
3
or is COR
3
or CO
2
R
3
;
Ar is phenyl, pyridyl, pyrimidyl or triazine, where AR may have from one to four substituents which are selected, independently of one another, from OR
4
, C
1
-C
8
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, halogen, CN, CO
2
R
3
, NO
2
, SO
2
R
3
, SO
3
R
3
, NR
3
R
4
, SO
2
NR
3
R
4
, SR
3
, CF
3
, CHF
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
1
-C
8
-alkyl, halogen, OC
1
-C
8
-alkyl, OH, NO
2
or CF
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
3
receptor ligands which intervene regioselectively in the limbic system and, because of their low affinity for the D
2
receptor, have fewer side effects than classical neuroleptics, which are D
2
receptor antagonists. The compounds can therefore be used to treat disorders which respond to dopamine D
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 alkoxy, alkyl-amino etc.) means a straight-chain or branched alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms and, in particular, 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of one another, from OH and OC
1
-C
8
-alkyl.
Examples of an alkyl group are methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl etc.
Alkylene stands for straight-chain or branched radicals having, preferably, 2 to 15 carbon atoms, particularly preferably 3 to 10 carbon atoms.
The alkylene groups may comprise at least one of the abovementioned groups. This can—just like the double or triple bond mentioned—be arranged in the alkylene chain at any point or at the end of the chain so that it connects the chain to the triazole residue. The latter is preferred. When the alkylene group comprises a double or triple bond, it has at least three carbon atoms in the chain.
Halogen is F, Cl, Br, I and, in particular, Cl, Br, I.
R
1
and R
2
are preferably, independently of one another, H, C
1
-C
8
-alkyl, NR
3
R
4
or OR
4
.
Ar can have one, two, three or four substituents. They are preferably selected, independently of one another, from halogen, CF
3
, CHF
2
, NR
3
R
4
, OR
4
, NO
2
, C
1
-C
8
-alkyl, OC
1
-C
8
-alkyl, SR
3
and CN, where R
3
and R
4
have the abovementioned meanings.
If one of the substituents of Ar is C
1
-C
8
-alkyl, a branched radical, in particular the isopropyl or t-butyl group, is preferred.
Ar preferably has at least one substituent and is, in particular,
where D
1
, D
2
and D
3
are, independently of one another, CR or N, and R, X and Y are H or are the substituents of the radical Ar indicated above or below.
Ar is preferably unsubstituted or substituted phenyl, 2-, 3- or 4-pyridinyl or 2-, 4(6)- or 5-pyrimidyl.
When one of the substituents of the radical Ar is a 5- or 6-membered heterocyclic ring, examples thereof are a pyrrolidine, piperidine, morpholine, piperazine, pyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole or thiadiazole residue.
When one of the substituents of the radical Ar is a carbocyclic radical, it is, in particular, a phenyl, cyclopentyl or cyclohexyl radical.
When Ar is fused to a carbocyclic or heterocyclic radical, Ar is, in particular, a naphthalene, di- or tetrahydronaphthalene, quinoline, di- or tetrahydroquinoline, indole, dihydroindole, benzimidazole, benzothiazole, benzothiadiazole, benzopyrrole or benzotriazole residue.
X is preferably
A preferred embodiment comprises compounds of the formula I where A is C
3
-C
10
-alkylene which comprises at least one group which is selected from O, S, NR
3
, cyclohexylene, in particular 1,4-cyxclohexylene, and a double or triple bond, where R
3
is as defined above.
Another preferred embodiment comprises compounds of the formula I where
R
1
is H, OR
4
where R
4
is H or C
1
-C
8
-alkyl, or C
3
-C
6
-cycloalkyl or C
1
-C
8
-alkyl which is unsubstituted or substituted by OH, OC
1
-C
8
-alkyl or halogen;
R
2
is H, C
1
-C
8
-alkyl which is unsubstituted or substituted by OH, OC
1
-C
8
-alkyl or halogen, or NR
3
R
4
where R
3
and R
4
are, independently of one another, H, phenyl-C
1
-C
8
-alkyl or C
1
-C
8
-alkyl, or OR
4
where R
4
is H or C
1
-C
8
-alkyl, or CF
3
;
A is as defined in claim 3, and
Ar is phenyl, pyridyl or pyrimidyl which may have one, two, three or four substituents which are selected from H, C
1
-C
8
-alkyl which is unsubstituted or substituted by OH, OC
1
-C
8
-alkyl or halogen, or OR
4
where R
4
is H, C
1
-C
6
-alykl [sic] which is unsubstituted or substituted by OH, OC
1
-C
8
-alkyl or halogen, or CHF
2
, CF
3
, CN, Halogen, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, phenyl, naphthyl and a 5- or 6-membered heterocyclic aromatic radical with 1 to 3 hetero atoms selected from O, N and S.
Another preferred embodiment comprises compounds of the formula I where
R
1
is H or C
1
-C
8
-alkyl which is unsubstituted or substituted by OH, OC
1
-C
8
-alkyl
Bialojan Siegfried
Drescher Karla
Hellendahl Beate
Lansky Annegret
Munschauer Rainer
Abbott Laboratories
Ford John M.
Keil & Weinkauf
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