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-10765693-B2
Publication Date
2020-09-08
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 (Form A and Form B) of Compound A, including their preparation methods and properties. These solid forms of Compound A can be crystalline, substantially free of amorphous content, and substantially free of impurities. The invention further includes pharmaceutical compositions containing these solid forms and methods for their use in treating diseases or conditions affecting the brain, central nervous system (CNS), or cardiovascular system, particularly injuries such as traumatic brain injury (TBI), stroke, neurodegenerative diseases, and cardiac ischemia.
The problem addressed is the lack of effective treatments for brain injuries, CNS injuries, heart and cardiovascular diseases, and neurodegenerative conditions. Neurons have a limited capacity to repair, so injuries often result in permanent damage and loss of function. Existing approaches do not adequately protect or restore neurons and related cell types, especially in the acute phase following injury or in long-term neurodegeneration.
The invention solves this problem by providing stable, crystalline, and pure polymorphic forms of Compound A that act as agonists at A3 and A1 adenosine receptors (and potentially P2Y1 receptors), promoting neuroprotective, neurorestorative, and cardioprotective effects. These forms are suitable for pharmaceutical formulation and administration, enabling modulation of cell survival pathways in neurons, glial cells, astrocytes, and other relevant cell types after injury or in chronic disease.
Claims Coverage
There are two primary independent inventive features in the claims, each covering a different solid form of Compound A.
Solid form of Compound A (Form A or equivalent)
- A solid form of Compound A, including crystalline forms, that is substantially free of amorphous Compound A and impurities. - The solid form can be characterized by having two peaks in its XRPD at about 8.0 and about 13.1 degrees 2-theta or an XRPD pattern substantially similar to that shown in FIG. 1. - Includes pharmaceutical compositions comprising this solid form and a pharmaceutically acceptable carrier, excipient, or adjuvant.
Solid form of Compound A (Form B or equivalent)
- A solid form of Compound A, including crystalline forms, that is substantially free of amorphous Compound A and impurities. - The solid form can be characterized by XRPD peaks at about 9.5, about 10.5, and about 13.8 degrees 2-theta or an XRPD pattern substantially similar to that shown in FIG. 10. - Includes pharmaceutical compositions comprising this solid form and a pharmaceutically acceptable carrier, excipient, or adjuvant.
The inventive features cover specific stable solid polymorphic forms of Compound A (Form A and Form B), their crystallographic characteristics, purity requirements, and their use in pharmaceutical compositions.
Stated Advantages
The solid forms of Compound A impart improved aqueous solubility, stability, and ease of formulation.
The crystalline forms are substantially free of impurities and amorphous content, ensuring purity and consistency.
Form A is moderately hygroscopic, stable, hydrated, and remains unchanged under high humidity, enhancing suitability for pharmaceutical use.
Form B is moderately hygroscopic, stable, unsolvated, and anhydrous, and maintains its crystalline form under various humidity conditions.
The compounds are useful for treating or lessening the severity of diseases and disorders of the brain, CNS, or cardiovascular system.
Documented Applications
Treatment, amelioration, or promotion of recovery from brain injuries, such as traumatic brain injury (TBI), concussion, stroke (ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, cerebral vasospasm, transient ischemic attacks), or partial/total spinal cord transection.
Promotion of neuroprotection and neurorestoration in patients suffering from neurodegenerative diseases and conditions, including Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Multiple Sclerosis, amyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy (CTE), and neurodegeneration due to genetic disorders, aging, virus, alcoholism, tumor, toxin, or repetitive brain injuries.
Treatment of heart or cardiovascular diseases, including 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 of conditions associated with brain injury or neurodegenerative disease, such as epilepsy, migraine, radiation damage, depression, mood or behavioral changes, dementia, memory loss, impaired speech, cognitive difficulties, vertigo, dysarthria, dysphagia, ocular abnormalities, tinnitus, hearing loss, attention deficit, and disorientation.
Treatment of autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease, intraocular hypertension, glaucoma, otic disorders, Meniere's disease, endolymphatic hydrops, progressive hearing loss, dizziness, pain control, type 2 diabetes, gastrointestinal conditions, and deficits in CNS function, learning, or cognition.
Treatment, amelioration, or prevention of addictive disorders and behavioral addictions, including addictions to prescription or recreational drugs such as heroin, cocaine, alcohol, opioids, nicotine, amphetamines, and treatment of compulsive or behavioral disorders such as OCD, Tourette syndrome, trichotillomania, eating disorders, and technology addiction.
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