Benzene derivative
Inventors
NOJIMA, SHOJI • Sasaki, Kenji • Kambe, Tohru • Konemura, Takashi • Goto, Yoshikazu
Assignees
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Publication Number
US-12258308-B2
Publication Date
2025-03-25
Expiration Date
Abstract
A compound represented by general formula (I) (in the formula, all symbols are as described in the description) or a salt thereof has a potent nerve-protecting and/or -repairing activity, and therefore can be used as a therapeutic agent for neuropathy (e.g., chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, periarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, entrapment neuropathy, peripheral neuropathy associated with the administration of a chemotherapeutic drug, or peripheral neuropathy associated with Charcot-Marie-Tooth disease).
Core Innovation
The invention relates to compounds of the invention defined by general formulae (I-i) through (I-1-D), including isomer scope and pharmaceutically acceptable forms such as salts, solvates, N-oxides, cocrystals, and prodrugs. The disclosure includes defined substituents and ring variables, and preferred embodiments within that chemical scope, including benzenesulfonamide-containing structures.
A key aspect is use of 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid, including a salt thereof, for nerve-protecting and/or -repairing activity. The disclosed activity includes promoting Schwann cell myelination and preventing and/or treating neuropathies, including peripheral neuropathy and central neuropathy.
The invention further relates to promoting differentiation of a Schwann cell by contacting a cell with 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof. The disclosure describes Schwann cell differentiation characterized by MAG immunostaining and associates the compounds with biological effects connected to Schwann cell differentiation and glial cells, including myelination of Schwann cells.
The invention also relates to preventing or treating neuropathy by administering 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof to a mammal, including a streptozotocin-induced diabetic peripheral neuropathy model with von Frey filament nociceptive threshold measurements. The disclosure further includes a benzene-derivative compound defined by a general formula (I) and salts thereof, with multiple general and sub-general formula embodiments and representative specific compounds.
Claims Coverage
The document contains two independent claims. The claim set covers a Schwann cell differentiation method and a neuropathy prevention or treatment method, both centered on 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof.
Schwann cell differentiation by contacting
A method of promoting differentiation of a Schwann cell by contacting a cell with 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof.
Preventing or treating neuropathy by administering
A method for preventing or treating neuropathy by administering an effective amount of 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof to a mammal.
Across the independent claims, the inventive coverage centers on using the same named benzenesulfonamide-containing propanoic acid or its salts to promote Schwann cell differentiation and to prevent or treat neuropathy through administration to a mammal, including central neuropathy and peripheral neuropathy.
Stated Advantages
Nerve-protecting activity.
Nerve-repairing activity.
Promotion of Schwann cell myelination.
Promotes differentiation of a Schwann cell.
Prevents or treats neuropathy.
Enhanced MAG/cell nuclei ratio reported for multiple examples in a Schwann cell differentiation promotion assay.
Improved or sustained analgesic effects reported in a streptozotocin-induced diabetic peripheral neuropathy model using von Frey filament nociceptive threshold measurements.
Potent nerve-protecting/nerve-repairing activity for neuropathy.
Low reactive metabolite (QA-GSH adduct) concentrations for selected examples as measured by LC/MS/MS.
Low teratogenic risk probability for identified examples based on Hand1-EST teratogenicity/toxicity assessment.
Nociceptive threshold effects in a streptozotocin model.
Documented Applications
Promoting differentiation of Schwann cells by contacting a cell with 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof.
Preventing or treating neuropathy in a mammal, including peripheral neuropathy and central neuropathy.
Peripheral neuropathy indications including diabetic neuropathy, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, carpal tunnel syndrome, Charcot-Marie-Tooth disease, and disease associated with neuropathic pain.
Central neuropathy including amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis.
In vitro Schwann cell differentiation promotion assay using MAG immunostaining and calculation of a differentiation promotion rate.
In vivo treatment or assessment in a streptozotocin-induced diabetic peripheral neuropathy model with von Frey filament nociceptive threshold measurements.
Reactive metabolite assessment via LC/MS/MS detection of QA-GSH adduct formation using human liver microsomes.
Teratogenicity/toxicity assessment using Hand1-EST with identification of low teratogenic risk examples.
Prophylaxis and treatment of neuropathy, including peripheral neuropathy subtypes such as chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré syndrome, diabetic peripheral neuropathy, and chemo/drug/toxin-associated neuropathies.
Peripheral neuropathy associated with Charcot-Marie-Tooth disease.
Peripheral neuropathy associated with an infectious disease.
Peripheral neuropathy associated with the ingestion of a heavy metal, an organic solvent, a toxic substance, or an alcohol.
Treatment context for central neuropathy, including amyotrophic lateral sclerosis.
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