Co-crystal forms of a novobiocin analog and proline
Inventors
Jiang, Xin • Walling, John Allen • Bevill, Melanie J. • Seadeek, Christopher S. • Smit, Jared P.
Assignees
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Publication Number
US-11401294-B2
Publication Date
2022-08-02
Expiration Date
Abstract
Disclosed are co-crystal forms of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-acetamide and L-proline or D-proline, their pharmaceutical compositions, processes of manufacture, and methods of use for treating neurodegenerative disorders such as diabetic peripheral neuropathy.
Core Innovation
The invention is directed to co-crystal forms made from N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide and L-proline, and also D-proline, including co-crystal forms and solvate co-crystal forms characterized by specific X-ray powder diffractogram peaks under Cu-Kα radiation parameters. Material A is defined as a co-crystal of the acetamide with L-proline in a 1:1 ratio, while Form B and Form D are defined by distinct X-ray powder diffractogram peak sets.
The disclosure further specifies additional named solid forms based on different proline stereochemistry and/or solvate components, including an acetone solvate co-crystal form and a solvate co-crystal form including methyl ethyl ketone and pyrazine. Form C is defined as a co-crystal of the acetamide with L-proline acetone solvate in a 1:1:1 ratio and is characterized by its X-ray powder diffractogram peaks, and Form G is defined as a co-crystal including methyl ethyl ketone and pyrazine in a stated molar ratio and is characterized by a distinct X-ray powder diffractogram peak set.
The invention also encompasses pharmaceutical compositions and therapeutic use by administering therapeutically effective amounts of at least one specified co-crystal selected from the defined forms to treat a neurological disorder in a subject. The treated neurological disorder is described as being among a list of neurological disorders, including diabetic peripheral neuropathy as described in the provided summary, as well as other enumerated neurological disorders in the provided claim set.
Claims Coverage
The partial claim set provides two independent claims: one directed to a composition containing specified proline co-crystal forms defined by X-ray powder diffractogram peak sets, and one directed to a method of treating a neurological disorder by administering therapeutically effective amounts of at least one specified co-crystal form. Across these independent claims, the inventive coverage is anchored by the identity of the acetamide with L-proline/D-proline and specified solvate components, and by form-defining X-ray powder diffractogram peak sets under Cu-Kα radiation parameters.
Co-crystal composition defined by form-specific X-ray powder diffractogram peaks
A composition comprising a co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide and L-proline, characterized by an X-ray powder diffractogram comprising specified peaks for Form B and Form D.
Treating neurological disorder by administering defined co-crystal forms characterized by X-ray powder diffractograms
A method for treating a neurological disorder in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of at least one cocrystal selected from co-crystals of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide and L-proline or D-proline, including Material A, Form B, Form C, Form D, Form G, and a 4a/D-proline co-crystal, each characterized by specified X-ray powder diffractogram peaks determined using Cu-Kα radiation parameters.
Across the independent claims, the main inventive content lies in defined co-crystal and solvate co-crystal compositions of the specified acetamide with proline stereochemistry and specified solvate components, where each form is characterized by specified X-ray powder diffractogram peak sets, and in using these defined co-crystal forms to treat a neurological disorder by administering a therapeutically effective amount to a subject.
Stated Advantages
Enhances bioavailability versus amorphous 4a (reported ~1.5–2×).
Selective, high-yield co-crystallization enriches the α-anomer (4a).
Improves purity with HPLC enrichment from ~90% to ≥95–99% depending on processing.
Documented Applications
Treating neurodegenerative disorders, notably diabetic peripheral neuropathy.
Treating a neurological disorder in a subject, where the neurological disorder is selected from epilepsy, multiple sclerosis, spinal cord injury, schizophrenia, depression, bipolar disorder, autism, and post-traumatic/posttraumatic stress disorder.
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