Methods of treating or controlling cytotoxic cerebral edema consequent to an ischemic stroke
Inventors
Pelletier, Marc F. • Farr, George William • Mcguirk, Paul Robert • Hall, Christopher H • Boron, Walter F.
Assignees
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Publication Number
US-11873266-B2
Publication Date
2024-01-16
Expiration Date
Abstract
The present invention relates to the use of selective aquaporin inhibitors, e.g., of aquaporin-4 or aquaporin-2, e.g., certain phenylbenzamide compounds, for the prophylaxis, treatment and control of aquaporin-mediated conditions, e.g., diseases of water imbalance, for example edema (particularly edema of the brain and spinal cord, e.g., following trauma or ischemic stroke, as well as the edema associated with glioma, meningitis, acute mountain sickness, epileptic seizures, infections, metabolic disorders, hypoxia, water intoxication, hepatic failure, hepatic encephalopathy, diabetic ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease, and lupus cerebritis, as well as edema consequent to microgravity and/or radiation exposure, as well as edema consequent to invasive central nervous system procedures, e.g., neurosurgery, endovascular clot removal, spinal tap, aneurysm repair, or deep brain stimulation, as well as retinal edema), as well as hyponatremia and excess fluid retention, and diseases such as epilepsy, retinal ischemia and other diseases of the eye associated with abnormalities in intraocular pressure and/or tissue hydration, myocardial ischemia, myocardial ischemia/reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, and neuromyelitis optica, as well as migraines, as well as to novel assays for identifying aquaporin inhibitors.
Core Innovation
The invention relates to selective aquaporin inhibitors based on phenylbenzamide compounds, including phenylbenzamide derivatives for targeting aquaporin-mediated water-imbalance conditions. The patent focuses on selective inhibition of aquaporin-4 (AQP4) and/or aquaporin-2 (AQP2) using phenylbenzamide structures including a formula 1a framework with defined substituent selections. Hydrolysable acyl groups are included via physiologically hydrolysable and acceptable acyl substituent selections and allowance for free or pharmaceutically acceptable salt form.
The patent addresses cytotoxic cerebral edema consequent to ischemic stroke in a human patient, including conditions characterized as water-imbalance and other edema-related disorders. The background context describes aquaporin roles in cytotoxic edema pathways and emphasizes that there is a lack of prior validated aquaporin inhibitors for these indications. The invention is positioned as prophylaxis, treatment, or control of aquaporin-mediated water-imbalance conditions.
The disclosed approach combines phenylbenzamide administration with reperfusion therapy procedures, specifically treating the human patient with intravenous thrombolysis and/or mechanical clot removal. In the provided claim set, phenylbenzamide of formula 1a is administered according to defined substituent selections for R1, R2, R3, R4, R5, and R6, including defined allowable halogen and trifluoromethyl choices and allowance of physiologically hydrolysable and acceptable acyl at R6. Dependent scope further specifies administration timing windows relative to stroke onset and, in some cases, specifies thrombolysis using rtPA.
Claims Coverage
The identified independent claim centers on administering a phenylbenzamide of formula 1a, together with treating the patient using intravenous thrombolysis and/or mechanical clot removal. Dependent claim refinements constrain compound substituent selections, formulation, timing windows, and thrombolysis agent details.
Phenylbenzamide of formula 1a for cytotoxic cerebral edema
A method of treating or controlling cytotoxic cerebral edema consequent to an ischemic stroke in a human patient in need thereof, wherein the method comprises administering to the human patient a phenylbenzamide of formula 1a with R1 selected from trifluoromethyl, chloro, fluoro, and bromo; R3 and R5 each selected from trifluoromethyl, chloro, fluoro, and bromo; R2 and R4 both H; and R6 selected from H and physiologically hydrolysable and acceptable acyl, in free or pharmaceutically acceptable salt form.
Combination with intravenous thrombolysis and/or mechanical clot removal
Treating the human patient with intravenous thrombolysis and/or mechanical clot removal as part of the method for treating or controlling cytotoxic cerebral edema consequent to an ischemic stroke after administering the phenylbenzamide of formula 1a.
The main inventive features are administration of a phenylbenzamide of formula 1a with specific substituent selections, including physiologically hydrolysable and acceptable acyl at R6, and combination with treating the patient using intravenous thrombolysis and/or mechanical clot removal.
Stated Advantages
Reduced cerebral edema.
Improved survival/neurological outcomes.
Documented Applications
Prophylaxis, treatment, or control of aquaporin-mediated water-imbalance conditions, including cytotoxic cerebral edema consequent to an ischemic stroke in a human patient.
Treatment or control of cytotoxic cerebral edema consequent to ischemic stroke in a human patient with an approach that includes treating with intravenous thrombolysis and/or mechanical clot removal.
Phenylbenzamide-mediated aquaporin inhibition applied to edema/ischemia-related conditions across cerebral, spinal cord, retinal, and optical nerve settings, including stroke and hypoxia, and also including microgravity and radiation exposure.
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