Crystalline forms of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(r)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide as an irreversible inhibitor of menin-MLL interaction
Inventors
Somanath, Priyanka • Lu, Daniel • Kinoshita, Taisei • Law, Brian • Butler, Thomas • Palmer, James T. • Lin, Nan-Horng • TAN, Heow Meng • WONG, Angelina Sau Man • JIANG, Siyi • He, Hongyan
Assignees
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Publication Number
US-12018032-B2
Publication Date
2024-06-25
Expiration Date
Abstract
Described herein is N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (I) including crystalline forms, solvates, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions that include compound (I), as well as methods of using compound (I), alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
Core Innovation
The document discloses Compound A as a covalent menin-MLL interaction inhibitor and includes pharmaceutically acceptable salts, solvates, hydrates, unsolvated/anhydrous, and amorphous phase variants. The invention defines crystalline Form D of Compound A and characterizes it by X-ray powder diffraction (XRPD) with characteristic peaks at 18.5±0.1° 2θ, 19.6±0.1° 2θ, and 24.2±0.1° 2θ.
Additional characterization is described using XRPD and other analytical techniques, and storage or stability considerations for Form D are described under open and closed container conditions. The document also mentions deuterium analogs of Compound A and Compound P, and their variant forms, as part of the disclosed chemical scope.
The background and therapeutic context state the need for treating cancers using a menin-MLL interaction inhibitor, including treatment with or without specific driver gene mutations. The document explicitly lists ATM, Notch1, TP53, WT1, KMT2A, TET2, Del(13q), and Trisomy 12 in the treatment context.
Claims Coverage
The provided claim content centers on one material-defining independent claim directed to crystalline Form D of Compound A characterized by an XRPD pattern with specified 2θ peaks. The excerpt also includes dependent claim matter refining XRPD features, storage retention, pharmaceutical compositions, and medical methods of treatment by administration to a mammal.
Crystalline form D characterized by an XRPD peak set
Crystalline Form D of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) is characterized by an X-ray powder diffraction pattern comprising characteristic peaks at 18.5±0.1° 2θ, 19.6±0.1° 2θ, and 24.2±0.1° 2θ.
Additional XRPD characteristic peaks for form D
Crystalline Form D is further defined by an XRPD pattern including one to four additional characteristic peaks at 3.4±0.1° 2θ, 8.7±0.1° 2θ, 10.72±0.1° 2θ, and 15.6±0.1° 2θ.
XRPD pattern retention after storage
Crystalline Form D retains the same X-ray powder diffraction pattern after storage under specified open and closed container conditions.
Treatment by administering crystalline form D
A method of treating cancer in a mammal by administering a therapeutically effective amount of crystalline Form D.
Therapeutically effective dosing amounts for form D
Administration of crystalline Form D to a mammal in therapeutically effective amounts selected from discrete amounts including 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 325 mg, 500 mg, and 650 mg.
The claim coverage is anchored by identification of crystalline Form D of Compound A through an XRPD-defined peak set. Dependent matter further links the crystalline form to additional XRPD peaks, storage retention, and treatment of cancer in a mammal by administration of a therapeutically effective amount.
Stated Advantages
Enables characterization and identification of crystalline Form D via an XRPD pattern with defined characteristic peak angles.
Provides storage stability/retention of the XRPD pattern for at least one week under specified open/closed container conditions.
Supports oral pharmaceutical formulation use of crystalline Form D with pharmaceutically acceptable excipients.
Provides therapeutic use by inhibition of menin-MLL activity across autoimmune/inflammatory/heteroimmune diseases and cancers, including B-cell malignancies.
Documented Applications
Treating cancer in a mammal by administering a therapeutically effective amount of crystalline Form D of Compound A.
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