Co-crystal forms of a novobiocin analog and proline
AssigneeReata Pharmaceuticals, Inc.
InventorsXin Jiang, John Allen Walling, Melanie J. Bevill, Christopher S. Seadeek, Jared P. Smit
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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.
Claims44
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 (1:2), characterized by an X-ray powder diffractogram comprising the following peaks:
- 14.76, 16.86, 19.00, and 21.05 °2θ±0.20 °2θ as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å.
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 (1:2), characterized by an X-ray powder diffractogram comprising the following peaks:
- 9.20, 16.19, 18.45, and 24.51 °2θ±0.20 °2θ as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å.
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 acetone solvate (1:1:1), characterized by an X-ray powder diffractogram comprising the following peaks:
- 14.64, 17.53, 18.91, and 21.33 °2θ±0.20 °2θ as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å.
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, L-proline, methyl ethyl ketone, and pyrazine in a molar ratio of about 1:12:0.6:0.1, characterized by an X-ray powder diffractogram comprising the following peaks:
- 10.42, 14.62, 19.28, and 21.14 °2θ±0.20 °2θ as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å.
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 D-proline (1:1), characterized by an X-ray powder diffractogram comprising the following peaks:
- 11.77, 14.52, 19.54, and 21.23 °2θ±0.20 °2θ as determined on a diffractometer using Cu-Kα1 radiation at a wavelength of 1.5405929 Å.
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 (1:1), characterized by an X-ray powder diffractogram comprising the following peaks:
- 8.52, 16.33, 19.50, and 21.22 °2θ±0.20 °2θ as determined on a diffractometer using Cu-Kα1 radiation at a wavelength of 1.5405929 Å.
A method of increasing the concentration 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 (4a) relative to N-(2-(5-(((2S,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 (4b) in a starting composition comprising 4a and 4b, comprising contacting the starting composition with proline in a solvent, and subjecting the starting composition, proline, and solvent to crystallization conditions, whereby a co-crystal of 4a and proline is produced, wherein the bulk co-crystal exhibits a concentration of 4a that is higher than in the starting composition comprising 4a and 4b.
-47. (canceled)
Dependencies are inferred from the claim text.