Fluoroergoline analogs

Inventors

Cook, Robert O. • Zhang, Jian • Armer, Thomas A.

Assignees

MAP Pharmaceuticals Inc

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 relates to fluoroergoline derivatives having a defined chemical structure with variable substituents R1–R11, including compounds, salts, ion pairs, polymorphs, hydrates, solvates, and prodrugs. The disclosure includes novel fluoroergoline derivatives and 2-trifluoromethyl analogs of ergoline drugs, including methysergide, dihydromethysergide, ergocristine, dihydroergocristine, α/β-ergocristine, α/β-dihydroergocristine, and dihydroergocorine/dihydroergocorine, together with amide forms and related carboxylic acid precursors.

The invention also covers pharmaceutical compositions comprising the fluoroergoline derivatives and/or salts and formulations for multiple administration routes. The routes explicitly include oral administration, parenteral administration, topical administration, transdermal administration, nasal administration, nasal inhalation, and oral inhalation, and oral inhalation delivery devices include a nebulizer, a pressurized metered dose inhaler, and a dry powder inhaler.

The disclosure further describes biological profiling using receptor assays and receptor activity categories, including 5-HT2B receptor, 5-HT1B and 5-HT1D receptor selectivity, D2 receptor activity changes, and adrenergic receptor antagonism. The fluoroergoline derivatives are characterized by selective agonism of 5-HT1D and/or 5-HT1B without 5-HT2B agonism, together with antagonism and/or inhibition at adrenergic alpha2A and/or adrenergic alpha2B receptors, and reduced 5-HT2B agonist activity.

Claims Coverage

The consolidated content provides two independent claims, each directed to administering a therapeutically effective amount of a compound having the specified structure, or a salt, for migraine or for a symptom of ALS. Across the independent claims, the main inventive features are the specific fluoroergoline compound structure and salt forms, together with route-of-administration selection for the stated indications.

Overall, the claim coverage is directed to treatment methods using therapeutically effective amounts of the specified fluoroergoline derivatives, or salts, for migraine and ALS-symptom treatment, with administration limited to specified oral, parenteral, topical, transdermal, nasal, and oral inhalation routes.

Stated Advantages

Documented Applications