Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-02-23
2001-03-27
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S544000
Reexamination Certificate
active
06207662
ABSTRACT:
This application is the national phase under 35 U.S.C. §371 of prior PCT International Application No. PCT/EP97/04587 which has an International filing date of Aug. 22, 1997 which designated the United States of America.
The present invention relates to novel pharmaceutically active disubstituted heterocyclic compounds with high affinity for central dopaminergic receptors. The compounds of the present invention are antagonists of the dopamine D
4
receptor and are useful in the treatment of central nervous system disorders, especially psychotic disorders such as schizophrenia.
BACKGROUND
Molecular biological techniques have revealed the existence of several subtypes of the dopamine receptor. The dopamine D
1
receptor subtype has been shown to occur in at least two discrete forms. Two forms of the D
2
receptor subtype, and at least one form of the D
3
receptor subtype, have also been discovered. More recently, the D
4
(Van Tol et al.,
Nature
(London), 1991, 350, 610) and D
5
(Sunahara et al.,
Nature
(London), 1991, 350, 614) receptor subtypes have been described.
The “dopamine hypothesis” of schizophrenia predicts an increased activity of dopamine neurotransmission in the brain. This hypothesis is supported by observations that drugs, such as amphetamine and cocaine, which indirectly stimulate the endogenous dopamine system by a dopamine release and uptake inhibition are capable of eliciting a psychosis resembling acute paranoid schizophrenia. The fact that classical antipsychotic drugs produce their therapeutic effect by blocking central dopamine D
2
receptors also lends credence to the “dopamine hypothesis”. It is however a serious drawback to the classical anti-psychotic drugs that the blockage of dopamine D
2
receptors also leads to extrapyrimidal side-effects (EPS).
Clozapine is the only neuroleptic agent that improves the “positive” and “negative” symptoms of schizophrenia without producing EPS. The mechanism of action of Clozapine remains elusive, but has been proposed to be due, in part to a greater blockade of dopamine D
4
receptors compared to D
2
receptors, and also to a blockade of serotonin 5-HT2A receptors. It is considered that compounds which can interact selectively with the dopamine D
4
receptor subtype, whilst having a less pronounced action at the D
2
subtype will be less prone to give the side-effects associated with classical antipsychotic drugs while maintaining a beneficial level of antipsychotic activity.
The compounds of the present invention are antagonists of the dopamine D
4
receptor they are predicted to be useful for the treatment of psychotic disorders such as schizophrenia.
Dopamine receptors are important for many functions in the animal body. For example, altered functions of these participate in the genesis of psychosis, addiction, sleep, feeding, learning, memory, sexual behaviour, regulation of immunological responses and blood pressure. Since dopamine receptors control a great number of pharmacological events, compounds that act preferentially on the dopamine D
4
receptor may exert a wide range of therapeutic effects in humans. The compounds of the present invention may therefore also be useful for the treatment of conditions such as sleep disorders, sexual disorders, gastrointestinal disorders, various forms of psychosis (affective psychosis, nonorganic psychosis), personality disorders, psychiatric mood disorders, conduct and impulse disorders, polydipsia, bipolar disorders, dysphoric mania, anxiety and related disorders, obesity, emesis, learning disorders, memory disorders, Parkinson's disease, depression, neuroleptic malignant syndrome, hypothalamic pituitary disorders, congestive heart failure, chemical dependencies such as drug and alcohol addictions, vascular and cardiovascular disorders, ocular disorders (including glaucoma), dystonia, tardive dyskinesia, Gilles De La Tourette's Syndrome and other hyperkinesias, dementia, ischaemia, movement disorders such as akathesia, hypertension and diseases caused by a hyperactive immune system such as allergies and inflammation.
PRIOR ART
U.S. Pat. No. 4,088,814 describes certain morpholine derivatives having the formula
wherein A means ethylene or vinylene and X means optionally substituted phenyl. The compounds are claimed to have psychotropic activity, e.g. antidepressant and sedative activity. Some compounds show analgesic activity. Compounds described herein having a benzyl group attached in position 4 are used as intermediates for the preparation of the therapeutically active compounds.
GB patent No. 1.138.405 describes certain morpholine derivatives having the formula
wherein R
1
and R
2
means hydrogen or alkyl, R
3
means hydrogen, alkyl, alkenyl, or cycloalkyl, and X means an optionally substituted aryl radical. The compounds described herein possess depressant action on the central nervous system, and are said to be useful in the treatment of anxiety, neurotic states and epilepsy. Some of the compounds are said to possess anti-depressant activity.
The compounds described herein having a arylalkyl group attached in position 4 are used as intermediates for the preparation of the therapeutically active compounds.
A well known compound disclosed in the above patent in Viloxazine or 2-[(2-ethoxyphenoxy)methyl]morpholine. This compound have no or only low affinity for the central dopaminergic D
2
and D
4
receptors.
GB patent No. 1.310.236 describes certain morpholine derivatives which are useful as intermediates for the preparation of therapeutically active compounds.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide novel disubstituted heterocyclic compounds and pharmaceutically-acceptable acid addition salts thereof which are useful for the treatment of central nervous system disorders, or diseases responsive to the blockade of dopamine D
4
receptors, especially psychotic disorders such as schizophrenia.
Another object of the present invention is to provide pharmaceutical compositions comprising the novel disubstituted heterocyclic compounds being useful for above purposes.
Still another object of the present invention is to provide a method of treating disorders or diseases responsive to the blockade of dopamine D
4
receptors using the novel disubstituted heterocyclic compounds.
Additional objects will be obvious from the following description, and others will be obvious to one skilled in the art.
SUMMARY OF THE INVENTION
The invention then, inter alia, comprises the following, alone or in combination:
A compound of the formula
any of its enantiomers, or any mixture thereof, or a pharmaceutically acceptable acid addition salt thereof,
wherein
R
1
, R
2
, R
3
, R
4
, R
11
, R
12
, R
13
, R
14
, and R
15
each independently are hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, nitro, cyano, amino, acyl, aminocarbonyl, or acylamino;
R
5
is hydrogen, alkyl, alkoxyalkyl, phenylalkyl;
X is —CH
2
—Z—, —Z—CH
2
—, —NH—CO—, —CO—NH—, or —CH═CH—; wherein Z is O, S, CH
2
or NH;
Y is O, —CH
2
—W—, —W—CH
2
—; wherein W is O, or S;
and n is 0,1, or 2;
a compound as above which is
(±)-N-(4-chlorobenzyl)-2-(2-methoxy-4-chloro-phenoxymethyl)-morpholine, or (±)-2-[(4-chloro-2-methoxyphenoxy)methyl]-4-(4-chlorobenzyl)perhydro oxazepine or a pharmaceutically acceptable acid addition salt thereof.
a pharmaceutical composition, comprising an effective amount of a compound as any above, or a pharmaceutically acceptable acid addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent;
the use of a compound having the formula
any of its enantiomers, or any mixture thereof, or a pharmaceutically acceptable acid addition salt thereof,
wherein
R
1
, R
2
, R
3
, R
4
, R
11
, R
12
, R
13
, R
14
, and R
15
each independently are hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, nitro, cyano, amino, acyl, aminocarbonyl, or acylamino;
R
5
is hydrogen, alkyl, alkoxyalkyl, phenylalkyl;
X is —CH
2
—Z—, —Z—CH
2
—, —NH—CO—, —CO—NH—, or —CH═CH—; wherein Z is O, S, CH
2
or NH
Axelsson Oskar
Nielsen Elsebet Ostergaard
Peters Dan
Scheel-Kruger Jorgen
Birch & Stewart Kolasch & Birch, LLP
Coleman Brenda
NeuroSearch A/S
Raymond Richard L.
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