Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
1999-08-09
2001-04-03
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C514S255030, C514S256000, C514S315000, C514S322000, C514S339000, C514S394000, C544S295000, C544S319000, C544S333000, C544S362000, C544S370000, C546S193000, C546S194000, C546S208000, C546S210000, C546S256000, C548S302100, C548S302400, C548S335100
Reexamination Certificate
active
06211366
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain bridged 4-phenyl-2-aminomethylimidazoles which selectively bind to dopamine receptor subtypes. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in the treatment of affective disorders such as schizophrenia, depression as well as certain movement disorders such as Parkinsonism and dystonia. Furthermore compounds of this invention are useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.
2. Description of the Related Art
Schizophrenia or psychosis is a term used to describe a group of illnesses of unknown origin which affect approximately 2.5 million people in the United States. These disorders of the brain are characterized by a variety of symptoms which are classified as positive symptoms (disordered thought, hallucinations and delusions) and negative symptoms (social withdrawal and unresponsiveness). These disorders have an age of onset in adolescence or early adulthood and persist for many years. The disorders tend to become more severe during the patient's lifetime and can result in prolonged institutionalization. Within the United States of America, approximately 40% of all hospitalized psychiatric patients suffer from schizophrenia.
During the 1950's physicians demonstrated that they could successfully treat psychotic (schizophrenic) patients with medications called neuroleptics. This classification of antipsychotic medication was based largely on the activating (neuroleptic) properties of the nervous system by these drugs. Subsequently, neuroleptic agents were shown to increase the concentrations of dopamine metabolites in the brain. This finding suggested that altered neuronal firing of the dopamine system contributed in some way to the aberrant behavior observed in schizophrenic patients. Additional evidence indicated that dopamine could increase the activity of adenylate cyclase in the corpus striatum, an effect reversed by neuroleptic agents. Thus, cumulative evidence from these and later experiments strongly suggested that the neurotransmitter dopamine was involved in schizophrenia.
One of the major actions of antipsychotic medication is the blockade of dopamine receptors in brain. Several dopamine systems appear to exist in the brain and at least five classes of dopamine receptors appear to mediate the actions of this transmitter. These dopamine receptors differ in their pharmacological specificity and were originally classified on the basis of their ability to bind various dopaminergic ligands.
The butyrophenones are a class of drugs containing many potent antipsychotic drugs. Perhaps the most prominent member of this class of compounds is the antipsychotic drug haloperidol (1-(3-p-fluorobenzoylpropyl)-4-p-chlorophenyl-4-hydroxypiperidine). Haloperidol binds relatively weakly at the major dopamine receptor subtype which activates adenylate cyclase (commonly classified as the D
1
dopamine receptor). In contrast, haloperidol displayed binding affinity at a dopamine receptor subtype which suppressed the activity of adenylate cyclase (commonly classified as D
2
receptors) in the subnanomolar range.
Recently, three additional dopamine receptor subtypes have been identified using the often congruent sciences of receptor pharmacology and molecular biology. These new dopamine receptors have been labeled as D
3
, D
4
, and D
5
. The D
3
and D
4
subtypes are pharmacologically related to the D
2
receptor via their ability to suppress the activity of adenylate cyclase. Conversely, the D
5
receptor is classified as a “D
1
-like” dopamine subtype through its ability to stimulate cyclase activity.
Recently, a new group of drugs (such as sulpiride and clozapine) have been developed with a lesser incidence of extrapyramidal side effects (EPS) than classical neuroleptics. In addition, there is some indication that they may be more beneficial in treating negative symptoms in some patients. Since all D
2
blockers do not possess a similar profile, hypotheses underlying the differences have been investigated. Major differences have been detected in the anticholinergic actions of these drugs. It has also been suggested that the dopamine receptors in motor areas may differ from those in the limbic areas which are thought to mediate the antipsychotic responses. The existence of the D
3
, D
4
and D
5
and other as yet undiscovered dopamine receptors may contribute to this profile. Some of the atypical compounds possess similar activity at D
2
, D
3
and D
4
receptors. The examples of this patent fall into this general class of molecules.
Using molecular biological techniques it has been possible to clone cDNAs coding for each of the pharmacologically defined receptors. There are at least two forms of D
1
which have been identified as D
1
and D
5
, and two forms of D
2
, identified now as D
2
and D
4
dopamine receptors. In addition, there is at least one form of D
3
dopamine receptor.
International Publication No. WO 94/22839 describes certain 2-aminomethylbenzimidazoles as having affinity at dopamine receptors. The compounds of the present invention differ from those in WO 94/22839 in that the compounds of this invention possess a aromatic benzene ring fused in a [4,5-c] fashion to the benzimidazole substructure.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with dopamine receptor subtypes.
The invention provides pharmaceutical compositions comprising compounds of Formula I. The invention also provides compounds useful in treating affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism. Furthermore, compounds of this invention are useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. Since particularly dopamine D
3
and D
4
receptor subtypes are concentrated in the limbic system (Science, 265: 1034 (Taubes, 1994)) which controls cognition and emotion, compounds which interact with these receptors are useful in the treatment of cognitive disorders. Such disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders involving memory impairment or attention deficit disorders can also be treated with the compounds of this invention that interact specifically with dopamine D
3
and/or D
4
receptor subtypes. Accordingly, a broad embodiment of the invention is directed to compounds of Formula I:
wherein
A represents —CH═CH—, or A represents —X—CH
2
—, where X is CH
2
or oxygen, provided that when X is oxygen, the oxygen is adjacent the 6-membered ring;
R
1
, R
2
, R
3
and R
4
are the same or different and represent hydrogen, halogen, hydroxy, amino, aminosulfonyl, alkylaminosulfonyl, alkylsulfonyl, arylalkylsulfonyl, alkyl or 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; and
R
5
represents alkyl having 1-3 carbon atoms and R
6
is benzyl, optionally substituted with alkyl having 1-6 carbon atoms, alkoxy, hydroxy, or halogen; or
NR
5
R
6
represents heterocyclic six membered ring optionally substituted with alkyl having 1-6 carbon atoms, hydroxyl, halogen, aryl, alkylaryl where the alkyl portion is alkyl having 1-6 carbon atoms, or heteroaryl.
The invention also pertains to the use of compounds of general Formula I in the treatment of neuropsychological disorders. The pharmaceutical utility of compounds of this invention is indicated by the assays described below for dopamine receptor subtype affinity.
REFERENCES:
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patent: 4305954 (1981-12-01), Finzio
patent: 4461894 (1984-07-01), Omodei-Sale et al.
patent: 5214040 (1993-05-01), Cuberes-Altisent et al.
patent: 5409931 (1995-04-01), Caprathe et al.
patent: 5418237 (1995-05-01), Bottcher et al.
patent: 5447931 (1995-09-01), Baroni et al.
patent: 5773616 (1998-0
Thurkauf Andrew
Yuan Jun
Higel Floyd D.
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
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