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Publication Number
US-9365591-B2
Publication Date
2016-06-14
Expiration Date
Abstract
Provided herein are novel fluoroergoline derivatives and compositions thereof. In other embodiments, provided herein are methods of treatment, prevention, or amelioration of a variety of medical disorders such as, for example, migraine using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of agonizing receptors such as, for example, the 5-HT1D and/or the 5-HT1B receptor, without agonizing the 5-HT2B receptor using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of antagonizing or inhibiting activity at receptors such as, for example, the adrenergic alpha2A and/or the alpha2B receptors using the compounds and compositions disclosed herein.
Core Innovation
The invention concerns novel fluoroergoline derivatives and substituted fluoroergoline/ergoline derivative scaffolds defined by variable substituents R1–R11, including fluorinated alkyl substituents and fluorinated methyl substituents such as CF3 (2-trifluoromethyl) analogs. The disclosed compounds include pharmaceutically acceptable salts, ion pairs, polymorphs, solvates and hydrates, as well as esters, enol ethers, enol esters, and prodrugs.
The disclosure presents structural formulas including Formulas I and II and example compound structures for the specified fluoroergoline/ergoline derivatives, including 2-CF3-dihydroergotamine and related forms. It also specifies substituted derivatives corresponding to methysergide, dihydromethysergide, ergocristine, dihydroergocristine, α-/β-ergocristine, α-/β-dihydroergocristine, and dihydroergocorine.
The disclosed compounds are provided in pharmaceutical compositions and administration formats, including oral, parenteral, inhalation, and topical formats. The document describes receptor-directed modulation, including agonism at 5-HT1D and/or 5-HT1B with reduced or avoided 5-HT2B agonism, antagonism or inhibition at adrenergic alpha2A and alpha2B receptors, and reported receptor activity at adrenergic and dopamine receptors.
The patent additionally describes synthesis of 2-CF3-dihydroergotamine from dihydroergotamine using trifluoromethyl iodide to obtain the CF3-substituted product, with characterization by purity/HPLC and MS/NMR. It also reports a scalable high-yield synthesis route for CF3 installation on DHE mesylate, including preparative chromatography purification and final API purity/yield, together with in vitro pharmacology, metabolism, genotoxicity, ex vivo vasoconstriction studies, and inhalation and nasal formulations.
Claims Coverage
The provided claim set covers structure-defined compounds, including salts. Across the inputs, one claim is directed to a specific compound structure, and another broadly covers a fluoroergoline or fluoroergoline/ergoline derivative compound depicted by a specified structure, or a salt thereof.
Structure-defined compound and its salts
A compound depicted by a specified structure, and also a salt of that compound.
Structure-defined fluoroergoline compound or salt
A compound depicted by a specified fluoroergoline or fluoroergoline/ergoline derivative structure, or a salt thereof.
Claim coverage is limited to structure-defined compounds and salts thereof, with no additional independent-claim refinements available in the provided content.
Stated Advantages
No agonist activity at the human 5-HT2B receptor.
Competitive antagonism at the 5-HT2B receptor.
Agonist activity at 5-HT1B and 5-HT1D receptors with reported selectivity.
D2 receptor agonism.
Adrenergic receptor antagonism across multiple adrenergic subtypes.
Liver microsomes show slower clearance relative to DHE.
No significant mutagenicity in Ames/S. typhimurium reversion.
Reduced vasoconstriction indicated by minimal tension change in coronary arteries/saphenous veins compared with sumatriptan.
High-yield, scalable synthesis route with reported API purity and yield.
Documented Applications
Inhalation formulation applications, including MDI with HFA blends and DPI lactose blends, with reported formulation performance outcomes.
Nasal administration applications, including a nasal suspension composition with reported outcomes.
Migraine.
ALS.
Parkinson's disease.
Extra-pyramidal disorders.
Depression.
Nausea.
Restless legs syndrome.
Insomnia.
Aggression.
Huntington's disease.
Dystonia.
Parasomnia.
Hyperprolactinemia.
Receptor modulation, including functional effects reported in receptor activity/functional assays [procedural detail omitted for safety].
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