Polymorphic compounds and uses thereof
Inventors
Poe, Russell Birch • JONAITIS, David T. • Grove, Lisa Michelle
Assignees
Triclinic Labs Inc • Astrocyte Pharmaceuticals Inc
Publication Number
US-11324769-B2
Publication Date
2022-05-10
Expiration Date
2039-09-26
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Abstract
The present invention provides compounds and methods of use thereof for treatment of certain disorders and conditions, for example brain injuries such as stroke or traumatic brain injuries.
Core Innovation
The invention provides solid polymorphic forms of a compound designated as compound A, including specifically Form A (a hydrated, crystalline form) and Form B (an anhydrous, crystalline form), as well as methods for preparing and characterizing these solid forms. These forms are defined by their x-ray powder diffraction (XRPD) patterns, FT-IR and FT-Raman spectra, and solid-state 13C NMR spectra, and are described as stable, moderately hygroscopic materials suitable for pharmaceutical use. The invention further encompasses compositions containing these solid forms and their use with pharmaceutically acceptable carriers, excipients, or adjuvants.
The present invention addresses the need for effective treatments for conditions including brain injuries (such as stroke and traumatic brain injuries), neurodegenerative disease, and cardiovascular diseases, for which existing therapies are lacking or insufficient. The background emphasizes the high morbidity, mortality, and health care costs associated with these conditions, as well as the lack of neuronal regenerative capacity after injury.
By providing stable, well-characterized solid forms of compound A with suitable physical and chemical properties (such as improved stability and ease of formulation), the invention enables the development of effective pharmaceutical compositions aimed at treating, ameliorating, or promoting recovery from brain, CNS, and cardiovascular disorders. The invention also includes methods of using these solid forms to increase neuroprotection, neurorestoration, and cardioprotection in patients suffering from or at risk of these conditions.
Claims Coverage
There are three main inventive features in the independent claims related to crystalline forms of compound A and their pharmaceutical use.
Crystalline solid forms of compound A defined by XRPD
The solid, crystalline forms of compound A are defined by specific x-ray powder diffraction (XRPD) patterns with characteristic peak positions and intensities. For example, Form A is characterized by one or more peaks at about 8.0 and about 13.1 degrees 2-theta, while Form B is characterized by peaks at about 19.0, about 20.1, and about 21.5 degrees 2-theta, as specified in the claims and tables. These forms may be further characterized by the number of observed peaks from the provided lists.
Further physical characterizations of the solid forms
- The solid forms are described in claims by specific features such as: - Melting point at or near 196° C. - Hydration state (hydrated or anhydrous and non-solvated forms). - IR, Raman, or 13C NMR spectra with specified peaks, or spectra substantially as shown in specified figures. - Content of crystalline compound (at least 95% by weight in some claims). - Being substantially free of impurities.
Pharmaceutical compositions comprising the solid forms
A pharmaceutical composition comprising a solid form of compound A (as defined by the XRPD, IR, Raman, or NMR features above), together with a pharmaceutically acceptable carrier, excipient, or adjuvant.
The claims provide coverage for distinct crystalline forms of compound A with defined structural, spectroscopic, and physical characteristics, as well as their inclusion in pharmaceutical compositions for therapeutic uses.
Stated Advantages
The provided solid forms impart improved aqueous solubility, stability, and ease of formulation to compound A.
Form A and Form B of compound A are described as stable and moderately hygroscopic, remaining unchanged after exposure to varying humidity and maintaining crystalline structure.
The invention enables effective treatment, amelioration, or recovery from brain, CNS, and cardiovascular conditions by providing appropriately formulated, stable compounds.
Documented Applications
Treatment, amelioration, or promotion of recovery from brain injuries such as traumatic brain injury (TBI), concussion, blast injury, stroke, subarachnoid hemorrhage, cerebral vasospasm, and transient ischemic attacks (TIA).
Treatment of neurodegenerative conditions including Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Multiple Sclerosis, amyotrophic lateral sclerosis (ALS), and chronic traumatic encephalopathy (CTE).
Promotion or increase of neuroprotection, neurorestoration, or neuroregeneration in patients with brain, CNS, or neurodegenerative diseases.
Treatment of heart and cardiovascular diseases such as cardiac ischemia, myocardial infarction, cardiomyopathy, coronary artery disease, arrhythmia, myocarditis, pericarditis, angina, hypertensive heart disease, endocarditis, rheumatic heart disease, congenital heart disease, and atherosclerosis.
Treatment or prevention of addictions, addictive behaviors, behavioral addictions, compulsive disorders (including substance use disorders for drugs such as heroin, cocaine, alcohol, opioids, nicotine, and amphetamines), and withdrawal symptoms.
Treatment of conditions associated with neurodegeneration or brain injury such as epilepsy, migraine, collateral brain damage from radiation therapy, depression, cognitive difficulties, memory loss, behavioral changes, attention deficit, vertigo, impaired speech, tremors, and loss of coordination.
Treatment of autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease, intraocular hypertension, glaucoma, otic disorders (progressive hearing loss, vertigo, tinnitus), sleep disorders in the elderly, epilepsy, schizophrenia, pain mediated by the CNS, mood or behavioral changes, gastrointestinal conditions, cancer such as glioblastoma, and type 2 diabetes.
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