Crystalline salt forms of kappa opioid receptor antagonist and products and methods related thereto
Inventors
Van Dyke, Brian • Shi, Yawei • Ma, Mengya • VAN ORDEN, Lori Jean
Assignees
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Publication Number
US-12171758-B1
Publication Date
2024-12-24
Expiration Date
Abstract
Disclosed herein is a solid Form A of 1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine hydrochloride exhibiting at least X-ray lines (in degrees 2θ±0.2) at 4.30, 8.59, 12.88, 18.82 and 21.34 in a powder diffraction pattern when measured using Cu Kα radiation. The solid Form A is an antagonist of the kappa-opioid receptor (KOR) and is useful for treating conditions that benefit from the same. Compositions comprising the solid Form A, as well as related methods of use are also disclosed.
Core Innovation
The invention concerns a crystalline hydrochloride salt of Compound No. 142, identified as a solid Form A of 1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine hydrochloride (Navacaprant). Form A is defined by a powder X-ray diffraction pattern measured using Cu Kα radiation and exhibits at least X-ray lines at 2θ±0.2° including 4.30, 8.59, 12.88, 18.82 and 21.34.
Form A is also characterized by additional X-ray diffraction criteria, including “essentially the same” or “substantially free” conditions for specified X-ray lines. The disclosure includes XRPD comparisons across batches and among other HCl solid forms identified as A, B1, B3, B4, and C2, as well as solvated, wet, and desolvated stages.
The disclosure further relates Form A to pharmaceutical composition and therapeutic use for KOR antagonism. Pharmaceutical compositions include Form A with pharmaceutically acceptable carriers, diluents, and excipients, and are described in oral, parenteral, and topical dosage forms, including capsule, tablet, pill, ampoule, depot/implant, extended release, and lyophilized powders.
Claims Coverage
The independent claim is directed to the solid crystalline Form A defined by specific XRPD peak positions measured with Cu Kα radiation, with multiple dependent claims refining the diffraction pattern using additional lines, essential-same comparison to a figure, or substantially-free absence criteria. Other dependent claims extend coverage to pharmaceutical compositions containing the solid and to therapeutic methods, including lowering serum prolactin.
Crystalline Form A defined by Cu Kα XRPD peak set
A solid Form A of 1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine hydrochloride exhibiting at least X-ray lines (2θ±0.2°) at 4.30, 8.59, 12.88, 18.82 and 21.34 in a powder diffraction pattern when measured using Cu Kα radiation.
Substantially free absence constraint for specified XRPD lines
A solid Form A having a powder diffraction pattern substantially free of specified X-ray line positions at 2θ±0.2°.
Additional XRPD line requirement selected from a set
A solid Form A in which the powder diffraction pattern has at least X-ray lines (2θ±0.2°) at the listed 2θ positions and at least one additional X-ray line selected from a specified set of 2θ positions.
Essentially the same XRPD pattern as FIG. 13
A solid Form A in which the powder diffraction pattern is essentially the same as the X-ray pattern shown in FIG. 13.
Pharmaceutical composition containing the solid Form A
A pharmaceutical composition comprising the solid Form A together with a pharmaceutically acceptable carrier, diluent, or excipient.
Method of lowering serum prolactin by administering Form A or its composition
A method of lowering a subject’s serum prolactin levels by administering an effective amount of the solid Form A of claim 1 (or a pharmaceutical composition containing it) at a frequency and duration sufficient to achieve a beneficial effect.
Overall, the claim set first anchors protection on the specific crystalline Form A defined by Cu Kα XRPD lines at the stated 2θ±0.2° values, and then narrows or further defines Form A using additional diffraction-line constraints, substantially-free absence criteria, and an “essentially the same” match to FIG. 13. The dependent claims then broaden to pharmaceutical compositions containing the solid and to therapeutic use, including lowering serum prolactin.
Stated Advantages
Provides a defined crystalline solid Form A characterized by a reproducible powder diffraction signature using Cu Kα radiation.
Enables pharmaceutical use of the solid Form A in pharmaceutical compositions for KOR antagonism and treating neuropsychiatric and behavioral conditions, including reduction of serum prolactin.
Documented Applications
KOR antagonism, including treating neuropsychiatric and behavioral conditions.
Lowering a subject’s serum prolactin levels by administering Form A or a pharmaceutical composition containing it.
Pharmaceutical composition applications using Form A in oral, parenteral, and topical dosage forms, including depot/implant, extended release, and lyophilized powder forms.
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