Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-11
2003-06-17
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S264400, C548S263800, C548S205000, C514S384000
Reexamination Certificate
active
06579892
ABSTRACT:
The invention relates to triazole compounds and to the use of these compounds. These compounds possess valuable therapeutic properties and can be used for treating diseases which respond to the influence of dopamine D
3
receptor ligands.
Compounds of the type which is under discussion here and which possess physiological activity are already known. Thus, WO 94/25013; 96/02520; 97/43262; 97/47602; 98/06699; 98/49145; 98/50363; 98/50364 and 98/51671 describe compounds which act on the dopamine receptors. DE 44 25 144 A, WO 96/30333, WO 97/25324, WO 97/40015, WO 97/47602, WO 97/17326, EP 887 350, EP 779 284 A and Bioorg. & Med. Chem. Letters 9 (1999) 2059-2064 disclose further compounds which possess activity as dopamine D
3
receptor ligands. U.S. Pat. Nos. 4,338,453; 4,408,049 and 4,577,020 disclose triazole compounds which possess antiallergic or antipsychotic activity. WO 93/08799 and WO 94/25013 describe compounds of the type which is under discussion here and which constitute endothelin receptor antagonists. Additional triazole compounds, which inhibit blood platelet aggregation and which have a hypotensive effect are described in
Pharmazie
46 (1991), 109-112. Further triazole compounds which possess physiological activity are disclosed in EP 691 342, EP 556 119, WO 97/10210, WO 98/24791, WO 96/31512 and WO 92/20655.
Neurons obtain their information by way of G protein-coupled receptors, inter alia. There are a large number of substances which exert their effect by way of these receptors. One of them is dopamine.
A number of facts about the presence of dopamine, and its physiological function as a neuron transmitter, are known with certainty. Disturbances of the dopaminergic transmitter system result in diseases such as schizophrenia, depression and Parkinson's disease. These, and other, diseases are treated with drugs which interact with the dopamine receptors.
By 1990, two subtypes of dopamine receptor had been clearly defined pharmacologically, namely the D
1
and D
2
receptors.
More recently, a third subtype has been found, namely the D
3
receptor, which appears to mediate some of the effects of the antipsychotic and anti-Parkinson agents (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; M. Dooley et al., Drugs and Aging 1998, 12, 495-514).
Since D
3
receptors are chiefly expressed in the limbic system, it is assumed that while a selective D
3
ligand would probably have the properties of known antipsychotic agents, it would not have their dopamine D
3
receptor-mediated neurological side-effects (P. Sokoloff et al., Localization and Function of the D
3
Dopamine Receptor,
Arzneim. Forsch./Drug Res
. 42(1), 224 (1992); P. Sokoloff 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 consequently selective D
3
ligands.
The present invention relates, therefore, to the compounds of the formula I:
where
R
1
is H, C
1
-C
6
-alkyl, which may be substituted by OH, OC
1
-C
6
-alkyl, halogen or phenyl, C
3
-C
6
-cycloalkyl or phenyl;
R
2
is H, 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
1
-C
6
-alkylthio, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, C
3
-C
6
-cycloalkyl, halogen, CN, COOR
3
, CONR
3
R
4
, NR
3
R
4
, SO
2
R
3
, SO
2
NR
3
R
4
, or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered-heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are selected, independently of each other, from O, N and S, with it being possible for the aromatic radical to have one or two 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, COR
3
, NR
3
R
4
, NO
2
, SO
2
R
3
, SO
2
NR
3
R
4
and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy, NR
3
R
4
, CN, CF
3
, CHF
2
or halogen;
R
3
and R
4
are, independently of each other, H, C
1
-C
6
-alkyl, which may be substituted by OH, OC
1
-C
6
-alkyl, halogen or phenyl, or phenyl;
A is C
4
-C
10
-alkylene or C
3
-C
10
-alkylene which comprises at least one group Z which is selected from O, S, CONR
3
, COO, CO, C
3
-C
6
-cycloalkyl and a double or triple bond;
B is a radical of the following formula:
X is CH
2
or CH
2
CH
2
;
R
5
is H, C
1
-C
6
-alkyl, which may be substituted by OH, OC
1
-C
6
-alkyl, halogen or phenyl, C
3
-C
6
-cycloalkyl, C
2
-C
6
-alkenyl, which may be substituted by halogen (1 or 2 halogen atoms), or C
2
-C
6
-alkynyl;
R
6
, R
7
and R
8
are, independently of each other, selected from H, C
1
-C
6
-alkyl, which may be substituted by OH, OC
1
-C
6
-alkyl, C
1
-C
6
-alkylthio, halogen or phenyl, OH, C
1
-C
6
-alkoxy, SH, C
1
-C
6
-alkylthio, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, halogen, CN, NO
2
, SO
2
R
3
, SO
2
NR
3
R
4
, CONR
3
R
4
, NHSO
2
R
3
and NR
3
R
4
;
and the salts thereof with physiologically tolerated acids.
The compounds according to the invention are selective dopamine D
3
receptor ligands which act in the limbic system in a regioselective manner and which, as a result of their low affinity for the D
2
receptor, have fewer side-effects than do the classic neuroleptic agents, which are D
2
receptor antagonists. The compounds can therefore be used for treating diseases which respond to dopamine D
3
ligands, i.e. they are effective for treating those diseases in which affecting (modulating) the dopamine D
3
receptors leads to an improvement in the clinical picture or to the disease being cured. Examples of such diseases are diseases of the cardiovascular system and the kidneys, diseases of the central nervous system, in particular schizophrenia, affective disorders, neurotic stress and somatoform disorders, psychoses, parkinsonism, attention deficit disorders, hyperactivity in children, epilepsy, amnesic and cognitive disorders such as learning and memory impairment (impaired cognitive function), anxiety states, dementia, delirium, personality disorders, sleep disturbances (for example restless legs syndrome), disorders of the sex life (male impotence), eating disorders and addictive disorders. Moreover, they are useful in the treatment of stroke.
Addictive disorders include the pysychological disorders and behavioral disturbances caused by the abuse of psychotropic substances such as pharmaceuticals or drugs, and other addictive disorders such as, for example, compulsive gambling (impluse control disorders not elsewhere classified). Addictive substances are, for exampel: opioids (for example morphine, heroin, codeine); cocaine; nicotine; alcohol; substances which interact with the GABA chloride canal complex, sedatives, hypnotics or tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylendioxy-N-methylamphetamine (ecstasy); amphetamine and amphetamine-like substances such as methylphenidate or other stimulants including caffeine. Addictive substances of particular concern are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol.
The compounds according to the invention are preferably used for treating affective disorders; neurotic, stress and somatoform disorders and psychoses, e.g. schizophrenia.
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, alkylthio, 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
Blumbach Kai
Neumann-Schultz Barbara
Schöbel Dietmar
Starck Dorothea
Treiber Hans-Jörg
Abbott Laboratories
Keil & Weinkauf
Liu Hong
Raymond Richard L.
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