Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-20
2004-03-02
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253030, C514S254090, C514S217050, C514S218000, C514S252110, C514S253090, C514S254050, C514S217080, C514S235500, C514S323000, C514S339000, C514S252130, C514S254110, C540S575000, C540S598000, C540S602000, C544S121000, C544S361000, C544S373000, C544S357000, C544S364000, C544S370000, C544S371000, C544S124000, C544S129000, C544S376000, C546S201000, C546S277400
Reexamination Certificate
active
06699864
ABSTRACT:
The present invention relates to novel substituted phenyl-piperazine derivatives potently binding to the 5-HT
1A
receptor, pharmaceutical compositions containing these compounds and the use thereof for the treatment of certain psychiatric and neurological disorders. Many of the compounds of the invention are also potent serotonin reuptake inhibitors and/or D
3
/D
4
ligands and are thus considered to be particularly useful for the treatment of depression and psychosis.
BACKGROUND ART
Clinical and pharmacological studies have shown that 5-HT
1A
agonists and partial agonists are useful in the treatment of a range of affective disorders such as generalised anxiety disorder, panic disorder, obsessive compulsive disorder, depression and aggression.
It has also been reported that 5-HT
1A
ligands may be useful in the treatment of ischaemia.
An overview of 5-HT
1A
antagonists and proposed potential therapeutic targets for these antagonists based upon preclinical and clinical data are presented by Schechter et al.,
Serotottin,
1997, Vol. 2, Issue 7. It is stated that 5-HT
1A
antagonists may be useful in the treatment of schizophrenia, senile dementia, dementia associated with Alzheimer's disease, and in combination with SSRI antidepressants also to be useful in the treatment of depression.
5-HT reuptake inhibitors are well known antidepressant drugs and useful for the treatment of panic disorders and social phobia.
The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HT
1A
receptor antagonist has been evaluated in several studies (Innis, R. B. et al.,
Eur. J. Pharmacol.,
1987, 143, p 195-204 and Gartside, S. E.,
Br. J. Pharmacol.
1995, 115, p 1064-1070, Blier, P. et al,
Trends Pharmacol. Sci.
1994, 15, 220). In these studies, it was found that combined 5-HT
1A
receptor antagonists and scrotonin reuptake inhibitors would produce a more rapid onset of therapeutic action.
Dopamine D
4
receptors belong to the dopamine D
2
subfamily of receptors, which is considered to be responsible for the antipsychotic effects of neuroleptics. The side effects of neuroleptic drugs, which primarily exert their effect via antagonism of D
2
receptors, are known to be due to D
2
receptor antagonism in the striatal regions of the brain. However, dopamine D
4
receptors are primarily located in areas of the brain other than striatum, suggesting that antagonists of the dopamine D
4
receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine, which exerts higher affinity for D
4
than D
2
receptors, and is lacking extrapyramidal side effects (Van Tol et al.
Nature
1991, 350, 610; Hadley
Medicinal Research Reviews
1996, 16, 507-526 and Sanner
Exp. Opin. Ther. Patents
1998, 8, 383-393).
A number of D
4
ligands, which were postulated to be selective D
4
receptor antagonists (L-745,879 and U-101958) have been shown to posses antipsychotic potential (Mansbach et al.
Psychopharmacology
1998, 135, 194-200). However, recently it has been reported that these compounds are partial D
4
receptor agonists in various in vitro efficacy assays (Gazi et al.
Br. J. Pharmacol.
1998, 124, 889-896 and Gazi et al.
Br. J. Pharmacol.
1999, 128, 613-620). Furthermore, it has been shown that clozapine, which is an effective antipsychotic, is a silent antagonists (Gazi et al.
Br. J. Pharmacol.
1999, 128, 613-620).
Consequently, D
4
ligands, which are partial D
4
receptor agonists or antagonists, may have beneficial effects against psychoses.
Dopamine D
4
antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al.
Psychopharmacology
1999, 142, 78-84).
It has also been suggested that dopamine D
4
antagonists may be useful to reduce dyskinesia occurring as a result of the treatment of Parkinson's disease with L-dopa (Tahar et al.
Eur. J Pharmacol.
2000, 399, 183-186).
Dopamine D
3
receptors also belong to the dopamine D
2
subfamily of receptors, and they are preferentially located in limbic regions of the brain (Sokoloff et al.
Nature,
1990, 347, 146-151), such as the nucleus accumbens, where dopamine receptor blockade has been associated with antipsychotic activity (Willner
Int. Clinical Psychopharmacology
1997, 12, 297-308). Furthermore, an elevation of the level of D
3
receptors in the limbic part of schizophrenic brains has been reported (Gurevich et al.
Arch. Gen. Psychiatry
1997, 54, 225-32). Therefore, D
3
receptor antagonists may offer the potential for an effective antipsychotic therapy, free of the extrapyramidal side effects of the classical antipsychotic drugs, which primarily exert their effect by blockade of D
2
receptors (Shafer et al.
Psychopharmacology
1998, 135, 1-16; Schwartz et al.
Brain Research Reviews
2000, 31, 277-287).
Moreover, D
3
receptor blockade results in a slight stimulation in the prefrontal cortex (Merchant et al.
Cerebral Cortex
1996, 6, 561-570), which could be beneficial against negative symptoms and cognitive deficits associated with schizophrenia. In addition, dopamine D
3
antagonists can reverse D
2
antagonist-induced EPS (Millan et al.
Eur. J. Pharmacol.
1997, 321, R7-R9) and do not cause changes in prolactin (Reavill et al.
J. Pharmacol. Exp. Ther.
2000, 294, 1154-1165). Consequently, D
3
antagonistic properties of an antipsychotic drug could reduce the negative symptoms and cognitive deficits and result in an improved side effect profile with respect to EPS and hormonal changes.
Dopamine D
3
agonists have also been considered relevant in the treatment of schizophrenia (Wustow et al.
Current Pharmaceutical Design
1997, 3, 391-404).
Accordingly, agents acting on the 5-HT
1A
receptor, both agonists and antagonists, are believed to be of potential use in the therapy of psychiatric and neurological disorders and thus being highly desired. Furthermore, antagonists at the same time having potent serotonin reuptake inhibition activity and/or D
4
and/or D
3
activity may be particularly useful for the treatment of various psychiatric and neurological diseases.
Structural similar compounds to the compounds of the present invention have been described earlier.
Thiophene derivatives are described in WO 9902516 as ligands for the 5-HT
1A
-receptor.
WO 9726252 describes piperazinyl derivatives as insecticides.
WO 9514004 describes substituted alkylamino-indole derivatives as 5-HT
1A
, 5-HT
1B
and 5-HT
1D
-derivatives.
It has now been found that compounds of a certain class of phenyl-piperazine derivatives bind to the 5-HT
1A
receptor with high affinities. Furthermore, it has been found that many of these compounds have other highly beneficial properties as i.e. potent serotonin reuptake inhibition activity and/or affinity for the D
4
and/or the D
3
receptor.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to novel compounds of the general Formula I:
wherein Z represents NH, NR′″, O or S; R′″ represents hydrogen, C
1-6
-alkyl;
R
7
and R
8
independently represent hydrogen, halogen, C
1-6
-alkyl, C
3-8
-cycloalkyl, CN, CF
3
or C
1-6
-alkoxy; or R
7
and R
8
together form a 5- or 6-membered aryl or heteroaryl fused to the benzene-ring;
Y represents N, C or CH;
the dotted line represents an optional bond;
R
6
and R
6′
represent H or C
1-6
-alkyl;
X represents —O— or —S—
n is 2, 3, 4 or 5;
m is 2 or 3;
R
1
, R
2
, R
3
, R
4
and R
5
are independently selected from a group consisting of hydrogen, halogen, C
1-6
-alkyl, C
1-6
-alkenyl, C
1-6
-alkynyl, C
3-8
-cycloalkyl, aryl, hydroxy, hydroxy-C
1-6
-alkyl, C
1-6
-alkoxy, C
3-8
-cycloalkoxy, C
1-6
-alkylsulfanyl, acyl, NR
9
R
10
wherein R
9
and R
10
independently represent hydrogen, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkynyl, C
3-8
-cycloalkyl or aryl; or R
9
and R
10
together with the nitrogen to which they are attached form a 1-morpholinyl, 1-piperidinyl, 1-homopiperidinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolyl, or pyrazolyl, all of which may be further substituted with C
1-6
-alkyl;
Andersen Kim
Krog-Jensen Christian
Mikkelsen Gitte
Moltzen Ejner Knud
Rottländer Mario
Bernhardt Emily
Darby & Darby
H. Lundbeck A/S
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