Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1998-01-20
1999-09-07
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
514255, 514256, 514315, 514322, 514339, 514394, 544242, 544319, 544333, 544362, 544370, 546193, 546208, 546210, 546256, 546194, 5483021, 5483024, 5483351, C07D40314, C07D40114, C07D40106, C07D40306, C07D23502, A61K 3144
Patent
active
059489120
DESCRIPTION:
BRIEF SUMMARY
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 Parkinson 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 neuroiransmitter dopamine was involved in schizophrenia.
One of the major actions of anupsychotic 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-hvdroxypiperidine). Haloperidol binds relatively weakly at the major dopargnine receptor subtype which activates adenylate cyclase (commonly classified as the D.sub.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.sub.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.sub.3, D.sub.4, and D.sub.5. The D.sub.3 and D.sub.4 subtypes are pharmacologically related to the D.sub.2 receptor via their ability to suppress the activity of adenylate cyclase. Conversely, the D.sub.5 receptor is classified as a "D.sub.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 treati
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patent: 4075342 (1978-02-01), Sale et al.
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patent: 5773616 (1998-06-01), Yuan et al.
Thurkauf Andrew
Yuan Jun
Higel Floyd D.
Neurogen Corporation
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