11-OXO-10,11-dihydrodibenzo[B,F][1,4]thiazepine S-oxide derivatives and their use as dopamine D2 receptor antagonists
Inventors
Marugan, Juan Jose • Xiao, Jingbo • Ferrer, Marc • Southall, Noel Terrence • Free, R. Benjamin • Sibley, David Robert
Assignees
US Department of Health and Human Services
Publication Number
US-9550742-B2
Publication Date
2017-01-24
Expiration Date
2034-07-29
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Abstract
The disclosure includes compounds and pharmaceutically acceptable salts of Formula (I). Certain compounds and salts of Formula (I) are selective inhibitors of the Dopamine D2 receptor. The variables R1-R4, n, and L are defined herein. The disclosure also provides methods of synthesizing compounds of Formula (I) and pharmaceutical compositions containing compounds of Formula (I). Additionally the disclosure provides methods or treating patients suffering from central nervous system disorders, including Tourette's syndrome, bipolar disorder, hyperprolactinemia, tardive dyskinesia, Huntington's chorea, psychosis, depression, or schizophrenia.
Core Innovation
The invention provides compounds and pharmaceutically acceptable salts of dihydrobenzo[b,f][1,4]thiazepine-8-carboxamides of Formula I that selectively inhibit the dopamine D2 receptor. These compounds have defined substituents including R1-R4, n, and L as specified in the disclosure. The inventive compounds demonstrate selective affinity for the dopamine D2 receptor subtype, achieving significant potency and selectivity over closely related dopamine receptor subtypes such as D3 and D4. The compounds include various stereochemical forms and pharmaceutically acceptable salts.
The problem addressed is the lack of selective dopamine D2 receptor antagonists due to high conservation of the orthosteric binding site among dopamine receptor subtypes and other G-protein coupled receptors. Existing D2 receptor ligands often exhibit off-target activity, which contributes to side effects. Current antipsychotic drugs antagonizing D2 receptors typically lack selectivity and interact with other GPCRs, causing undesired adverse effects. There is a clinical need for highly selective dopamine D2 receptor antagonists that can provide therapeutic benefits with reduced side effects.
The disclosure further provides methods for synthesizing the compounds of Formula I and pharmaceutical compositions containing them. Methods of treating central nervous system disorders in patients, including Tourette's syndrome, bipolar disorder, hyperprolactinemia, tardive dyskinesia, Huntington's chorea, psychosis, depression, or schizophrenia, are also provided through selective antagonism of the dopamine D2 receptor using these compounds.
Claims Coverage
The patent contains multiple independent claims defining compounds of Formula I with various substituents, and pharmaceutical compositions and methods of treatment using these compounds. The main inventive features are extracted below from these compound claims and related pharmaceutical uses.
Selective dopamine D2 receptor antagonist compounds
The compounds of Formula I or their pharmaceutically acceptable salts are selective antagonists of the dopamine D2 receptor. They have specific chemical structures including substituents R1-R4, n, and L with defined values and restrictions, enabling selective binding and functional modulation of the D2 receptor over other dopamine receptors.
Defined chemical substituents and structural features
The compounds feature precise structural variations including R1 as C1-C6alkyl, C2-C6alkenyl, or cycloalkylalkyl; n as an integer from 1 to 4; and R2 as mono-, bi-, or tricyclic carbocyclic or heterocyclic groups with specified substitution patterns. Specific substitution patterns on R3 and R4 and defined linkages (L) contribute to stability and receptor selectivity.
Pharmaceutical compositions containing selective D2 antagonists
Pharmaceutical compositions are disclosed comprising a compound or salt of Formula I combined with pharmaceutically acceptable carriers suitable for various routes of administration, including oral, topical, parenteral, inhalation, sublingual, transdermal, and others.
Methods of treating central nervous system disorders
Methods of treating disorders such as Tourette's syndrome, bipolar disorder, hyperprolactinemia, tardive dyskinesia, Huntington's chorea, psychosis, depression, and schizophrenia through administering therapeutically effective amounts of the compounds or salts of Formula I are claimed.
The patent claims cover structurally defined selective dopamine D2 receptor antagonists of Formula I, pharmaceutical compositions comprising these compounds, and methods of treating CNS disorders mediated by dopamine D2 receptor antagonism.
Stated Advantages
The disclosed compounds provide high selectivity for the dopamine D2 receptor, reducing off-target interactions common in existing drugs.
Selective antagonism of the D2 receptor may reduce adverse effects caused by non-selective GPCR antagonists in antipsychotic therapies.
The compounds can serve as selective pharmacological probes to study dopamine receptor functions with improved in vivo selectivity.
They cross the blood-brain barrier and effectively occupy D2 receptors in the central nervous system at pharmacologically relevant doses.
Demonstrated in vivo selectivity to block D2 receptor-mediated responses without affecting D3 receptor-mediated functions.
Documented Applications
Treatment of central nervous system disorders including Tourette's syndrome, bipolar disorder, hyperprolactinemia, tardive dyskinesia, Huntington's chorea, psychosis, depression, and schizophrenia.
Use as selective pharmacological probes to investigate dopamine D2 receptor function.
Administration for reducing psychiatric symptoms, including schizophrenia and Tourette's symptoms.
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