Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
Inventors
Liu, Shuang • Molino, Bruce F. • Nacro, Kassoum
Assignees
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Publication Number
US-9034899-B2
Publication Date
2015-05-19
Expiration Date
Abstract
Novel aryl, heteroaryl, and non-aromatic heterocyle substituted tetrahydroisoquinolines are described in the present invention. These compounds are used in the treatment of various neurological and physiological disorders. Methods of making these compounds are also described in the present invention.
Core Innovation
The invention provides compounds of formula (I) having a carbon atom designated * in the R or S configuration. The compound is defined by multiple substituent variables with optional substitution patterns and group selections, including heteroaryl selections and non-aromatic heterocycle substituents, and the scope includes specific heteroaryl embodiments, including [1,2,4]triazolo[1,5-a]pyridinyl options. The structure further allows optional substitution counts via R14, with R8 being H or methyl.
The compounds include chiral tetrahydroisoquinoline compounds of formula (I) with defined stereochemistry and variable substituents, including specific heteroaryl selection and optional salt or oxide forms. The disclosed examples cover chiral tetrahydroisoquinoline derivatives having pyridazine/pyridinyl/pyridazinyl/triazolopyridine substituents, including forms with Boc protection and deprotection, and multiple salt forms such as HCl, trifluoroacetate, and L-tartrate.
The disclosure also includes single-crystal X-ray crystallography for specific salt forms, including unit cell parameters and refinement notes for L-tartrate and HCl salt polymorphs, and a crystalline form characterized as Form SA-1 with solid-state characterization using PXRD, DSC, and TGA. The compounds are stated to be used to treat neurological and psychiatric and physiological disorders through inhibition/selective binding at monoamine transporter proteins, including SERT, NET, and DAT.
Claims Coverage
The claims coverage includes independent claim coverage for formula (I) compounds with stereochemical designation and variable substituent sets, together with dependent claims that narrow substituent options and add pharmaceutical composition context. Across the independent claims, there are three main inventive feature groupings centered on chiral formula (I) compounds, a constrained heteroaryl-containing subset, and specific tetrahydroisoquinoline structures.
Stereodefined formula I compound with variable substituent scope
A compound of formula (I) wherein the carbon atom designated * is in the R or S configuration, and wherein R1, R2, R3, R4, R5, R6, R7, and R8 are defined by the provided groups and optional substitution patterns, including heteroaryl selection for R3 and optional substitution count constraints via R14.
Stereodefined formula I compound with constrained substituent sets and specified R3/R8 options
A compound of formula (I) wherein the carbon atom designated * is in the R or S configuration, R1 is H, methyl, or gem-dimethyl, R2 and R4 are defined by the provided limited sets, R3 is [1,2,4]triazolo[1,5-a]pyridinyl-6-yl optionally substituted by R14, R5 to R7 are independently selected from the provided limited sets, and R8 is H or methyl, with optional oxide/salt/solvate/prodrug forms.
Specific tetrahydroisoquinoline structures including oxide and pharmaceutically acceptable salts
A compound selected from specified tetrahydroisoquinoline-based structures, including an oxide thereof and a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with carrier and therapeutically effective amount
A pharmaceutical composition including a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of formula (I).
Overall, the claims define chiral formula (I) compounds with extensive substituent-variable definitions, including [1,2,4]triazolo[1,5-a]pyridinyl-6-yl and other heteroaryl options, and allow optional oxide, pharmaceutically acceptable salt, solvate, prodrug, isotopic, and stereoisomeric forms. Dependent claims further narrow substituent sets and include a pharmaceutical composition with a carrier and a therapeutically effective amount.
Stated Advantages
Used to treat neurological and psychiatric and physiological disorders via inhibition/selective binding at monoamine transporter proteins (SERT/NET/DAT).
Encompasses monoamine transporter concepts including dual and triple uptake inhibition.
Includes defined solid-state characterization for a specific crystalline form (Form SA-1) using PXRD, DSC, and TGA.
Documented Applications
Transporter binding (SERT/DAT/NET) evaluation.
Ex vivo occupancy assay.
In vivo behavioral assays including tail suspension, forced swim, and locomotor activity.
Single-crystal X-ray crystallography disclosure for specific salt forms including L-tartrate and HCl salt polymorphs.
Therapeutically treating neurological and psychiatric and physiological disorders using inhibition/selective binding at monoamine transporter proteins (SERT, NET, DAT).
Therapeutic methods including administration of therapeutically effective amounts for neurological/psychiatric disorders such as ADHD, MDD, OCD, PTSD, Parkinson’s disease, pain, premature ejaculation, obesity, and substance abuse.
Combination therapy described with serotonin 1A receptor antagonists and neurokinin-1 receptor antagonists.
Crystalline form characterization is documented for Form SA-1.
Primary binding assays for hSERT, hDAT, and hNET and an ex vivo occupancy assay.
In vivo behavioral assay descriptions including mouse tail suspension assay, rat forced swim assay, and locomotor activity.
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