Search

US-12616696-B2 - Crystalline forms of (p)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2h-[1,4′-bipyridin]-2-one

US12616696B2US 12616696 B2US12616696 B2US 12616696B2US-12616696-B2

Abstract

The present disclosure provides a crystalline form of the methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compound of the structure: XRPD, TGA, and DSC data on the crystalline form, as well as methods preparing the crystalline form, including a multi-kilo scale preparation. Also provided are pharmaceutical compositions and methods of treating p 38 mediated diseases, such as lymphoma and auto-inflammatory disease, including rheumatoid arthritis. and methods of maximizing the yield thereof comprising administering of the compound. Also provided is a method of maximizing the yield of said compound via a recycling procedure.

Inventors

  • Gary A. DeCrescenzo
  • John Robert Springer
  • Susan Landis Hockerman

Assignees

  • ACLARIS THERAPEUTICS, INC.

Dates

Publication Date
20260505
Application Date
20210326

Claims (12)

  1. 1 . A crystalline form of (P)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (Compound 49a) of the following structure: wherein the crystalline form of (P)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (Compound 49a) is Form A; and wherein Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising a characteristic peak at an angle expressed in degrees 2-theta (°2θ) of 9.78°±0.2°.
  2. 2 . The crystalline Form A of claim 1 , wherein the crystalline Form A is further characterized by an X-ray powder diffraction (XRPD) pattern comprising a characteristic peak at an angle expressed in degrees 2-theta (°2θ) of 15.51°±0.2°.
  3. 3 . The crystalline Form A of claim 1 , wherein the crystalline Form A is further characterized by an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at angles expressed in degrees 2-theta (°2θ) of 15.51°±0.2°, 19.60°±0.2°, and 25.92°±0.2°.
  4. 4 . The crystalline Form A of claim 1 , wherein the crystalline Form A is further characterized by an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at angles expressed in degrees 2-theta (°2θ) of 15.34°±0.2°, 15.51°±0.2°, 19.60°±0.2°, 20.57°±0.2°, 21.01°±0.2°, 25.92°±0.2°, 29.05°±0.2°, and 29.48°±0.2°.
  5. 5 . The crystalline Form A of claim 1 , wherein the crystalline Form A is further characterized by a Fourier transform infrared (FTIR) spectrum comprising characteristic peaks (cm −1 ) at 3486, 3072, 2982, 1656, 1605, 1592, 1571, 1546, 1525, 1476, 1457, 1429, 1385, 1380, 1350, 1296, 1237, 1214, 1184, 1130, 1103, 1051, 1044, 1005, 978, 964, 860, 840, 810, 793, 781, 755, 741, 703, and 669.
  6. 6 . The crystalline Form A of claim 1 , wherein the crystalline Form A is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an initial endothermic melting event with an onset temperature of 188° C., followed by an exothermic recrystallization event at 196° C., with a final sharp exothermic melting event at 254° C.
  7. 7 . The crystalline Form A of claim 1 , wherein the crystalline Form A is further characterized by a differential scanning calorimetry (DSC) thermogram comprising a single melting event at 192.6° C.
  8. 8 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of the crystalline Form A of claim 1 .
  9. 9 . The pharmaceutical composition of claim 8 , wherein the therapeutically effective amount is in the range of from 10 mg to 300 mg.
  10. 10 . The pharmaceutical composition of claim 9 , wherein the therapeutically effective amount is 50 mg.
  11. 11 . The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition is an oral pharmaceutical composition.
  12. 12 . The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition is formulated as a tablet.

Description

B. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application Serial No. 63,000,746, filed on Mar. 27, 2020; Ser. No. 63/015,241, filed on Apr. 24, 2020; Serial No. 63,018/954, filed on May 1, 2020; Ser. No. 63/022,301, filed on May 8, 2020; Ser. No. 63/022,298, filed on May 8, 2020; Ser. No. 63/024,160, filed on May 13, 2020; Ser. No. 63/053,903, filed on Jul. 20, 2020; Ser. No. 63/076,689, filed on Sep. 10, 2020; Ser. No. 63/126,173, filed on Dec. 16, 2020; Ser. No. 63/128,523, filed on Dec. 21, 2020; Ser. No. 63/136,080, filed on Jan. 11, 2021; Ser. No. 63/136,967, filed on Jan. 13, 2021; Ser. No. 63/138,672, filed on Jan. 18, 2021; Ser. No. 63/140,116, filed on Jan. 21, 2021; and Ser. No. 63/149,230, filed on Feb. 13, 2021, each of which is hereby incorporated by reference in its entirety. C. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT Not Applicable D. THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT Not Applicable E. INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC Not Applicable F. BACKGROUND OF THE INVENTION Not Applicable 1. Field of Invention Not Applicable 2. Description of Related Art Not Applicable G. BRIEF SUMMARY OF THE INVENTION The present disclosure includes embodiments directed to a compound of Formula (P)-Ia wherein: X is CH or N;R1 is selected from the group consisting of H, C1-C6 alkyl, fluoro, chloro, bromo, cyano, or —CF3;R2 is selected from the group consisting of H, methyl, cyano, or fluoro;R3 is selected from the group consisting of: R4 is selected from the group consisting of H, methyl, OH, and —OCH3;R5 is H or C1-C3 alkyl;m is 1 or 2;n is 0 or 1;p is 1; andq is 0 or 1 or a derivative thereof. Some embodiments are directed to a pharmaceutical composition comprising a compound of Formula (P)-Ia or a derivative thereof, and a pharmaceutically-acceptable carrier. In various embodiments, the pharmaceutical composition further comprises one or more additional pharmaceutically active compounds. In other embodiments, there is provided a method for treating a condition comprising administering to a subject a therapeutically effective amount of a compound of the present invention, alone or in combination with other pharmaceutically active compounds. In any embodiment, suitable conditions to be treated include, but are not limited to, autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, auto-inflammatory disorders, pain, atherosclerosis, diabetes, fibrotic diseases, metabolic disorders, cancer, neoplasia, leukemia, lymphoma, rheumatoid arthritis, and idiopathic pulmonary fibrosis. The present disclosure also provides methods for maximizing the synthetic yield of a compound having the structure of Formula (P)-Ia by equilibration or interconversion of a compound having the structure of Formula (M)-Ib: comprising heating a solution comprising the compound having the structure of Formula (M)-Ib to a temperature at which the compound equilibrates to form a mixture of atropisomers. The present disclosure includes embodiments directed to crystalline forms of Compound 49a, of the structure: The crystalline forms of Compound 49a can been characterized by one or more methods, including but not limited to, X-Ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Raman spectroscopy, infrared spectroscopy, solid-state NMR, and other analytical characterization techniques known in the art. Pharmaceutical compositions are often formulated with a crystalline solid of the active ingredient (API). The specific crystalline form of the API can have significant effects on properties such as stability, dissolution rate and bioavailability. Instability and poor solubility characteristics can limit the ability to formulate a composition with adequate shelf life or to effectively deliver a desired amount of drug over a given dosing timeframe. One strategy used to achieve the desired physical parameters is to identify the most stable polymorphic form of the API and to define the crystallization processes that would consistently produce the stable crystalline polymorph and avoid producing alternate solid forms, mixtures of polymorphs, hydrates or solvates that can compromise the stability and performance of the composition. Some embodiments are directed to a pharmaceutical composition comprising a crystalline form of Compound 49a and a pharmaceutically-acceptable carrier. In various embodiments, the pharmaceutical composition further comprises one or more additional pharmaceutically active compounds. In other embodiments, there is provided a method for treating a condition comprising administering to a subject a therapeutically effective amount of a crystalline form of Compound 49a of the present invention, alone or in combination with other pharmaceutically active compounds. In any embodiment, suitable conditions to be treated include,