8′-hydroxy-dihydroergotamine compounds and compositions

Inventors

Kellerman, Donald J. • Armer, Thomas • Zhang, Jian

Assignees

MAP Pharmaceuticals Inc

Abstract

8′-Hydroxy-Dihydroergotamine (8′-OH DHE) medicinal compounds, compositions, and dosage forms containing such compositions are provided. Also provided herein are methods of treatment, prevention, or amelioration of migraine disorders using the compounds, compositions, dosage forms and administration techniques disclosed herein.

Core Innovation

The invention relates to 8′-hydroxy-dihydroergotamine (8′-OH DHE) medicinal compounds and compositions for treating, preventing, or ameliorating migraine disease, condition or disorder symptoms. It is directed to administering a therapeutically effective dose of an 8′-OH DHE composition to a subject in need of migraine treatment. The disclosure frames migraine benefit in terms of symptom relief, including reduction of one or more migraine symptoms.

A receptor-targeting rationale is provided for 8′-OH DHE, including agonizing 5-HT1D and 5-HT1B while avoiding 5-HT2B-related fibrosis risk. The disclosure also includes antagonizing and inhibiting adrenergic α1/α2 receptors, and reducing dopamine receptor agonism to limit nausea and emesis. The stated approach ties pharmacological selectivity to reducing drug-induced side effects associated with migraine therapies.

The disclosure further emphasizes formulation and administration approaches for 8′-OH DHE, including oral pulmonary inhalation using DPI and pMDI, as well as other delivery routes. It also discusses achieving pharmacokinetic exposure by obtaining a therapeutically effective Cmax within T_max while keeping Cmax low to help avoid adrenergic/dopaminergic binding associated with side effects. Medicinal chemistry scope includes 8′-OH DHE derivatives with ergoline ring/peptide side chain substitutions, along with receptor-binding and functional profiling and composition examples.

Claims Coverage

The independent claim covers a migraine method defined by administering a therapeutically effective dose of an 8′-OH DHE composition, with multiple dependent refinements that add key inventive features including treatment outcome limitations, side-effect exclusion, and quantitative pharmacokinetic constraints.

Overall claim coverage centers on administering a therapeutically effective dose of an 8′-OH DHE composition to treat, prevent or ameliorate migraine symptoms, with dependent features that specify inhalation delivery devices, broaden dosage-form options, exclude drug-induced side effects, and impose a Cmax threshold of less than 500 pg/mL.

Stated Advantages

Documented Applications

No documented applications found