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US-12624040-B2 - Compositions of substituted pyrazolopyrimidines and uses thereof

US12624040B2US 12624040 B2US12624040 B2US 12624040B2US-12624040-B2

Abstract

Pharmaceutical formulations comprising substituted pyrazolopyrimidines are disclosed herein. Also disclosed are amorphous solid dispersions comprising substituted pyrazolopyrimidines, processes for preparing these amorphous solid dispersions, pharmaceutical compositions comprising such dispersions, and methods of use thereof.

Inventors

  • Hanlan Liu
  • Robert M. Wenslow, Jr.

Assignees

  • KSQ Therapeutics, Inc.

Dates

Publication Date
20260512
Application Date
20210114

Claims (20)

  1. 1 . An amorphous solid dispersion, comprising a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R is C 1-3 alkyl; and X 1 and X 2 are independently selected from the group consisting of N and C, wherein the compound is in a solid substantially amorphous form and is dispersed in a polymer.
  2. 2 . The amorphous solid dispersion according to claim 1 , wherein the compound is 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzyl)-1H-pyrazolo[3,4-d]pyrimidine of Formula (II)
  3. 3 . The amorphous solid dispersion according to claim 1 , wherein the compound is 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzyl)-1H-pyrazolo[3,4-d]pyrimidine of Formula (III)
  4. 4 . The amorphous solid dispersion according to claim 1 , wherein the polymer is selected from the group consisting of polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), poly (ethylene glycol) (PEG), poly (ethylene oxide) (PEO), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), copovidone, hydroxypropyl methylcellulose acetate succinate, methacrylic acid copolymer, polyacrylates and mixtures thereof.
  5. 5 . The amorphous solid dispersion according to claim 1 , wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, and methacrylic acid copolymer.
  6. 6 . The amorphous solid dispersion according to claim 5 , wherein the polymer is hydroxypropyl methylcellulose acetate succinate.
  7. 7 . The amorphous solid dispersion according to claim 5 , wherein the polymer is poly (methacrylic acid)-co-methyl methacrylate.
  8. 8 . The amorphous solid dispersion according to claim 2 , wherein the compound of Formula II is dispersed in hydroxypropyl methylcellulose acetate succinate.
  9. 9 . The amorphous solid dispersion according to claim 2 , wherein the compound of Formula II is dispersed in poly (methacrylic acid)-co-methyl methacrylate.
  10. 10 . The amorphous solid dispersion according to claim 3 , wherein the compound of Formula III is dispersed in hydroxypropyl methylcellulose acetate succinate.
  11. 11 . The amorphous solid dispersion according to claim 3 , wherein the compound of Formula III is dispersed in poly (methacrylic acid)-co-methyl methacrylate.
  12. 12 . The amorphous solid dispersion according to claim 4 , wherein the polymer is present in an amount of between about 40% and about 95% of the total weight of the solid dispersion.
  13. 13 . The amorphous solid dispersion according to claim 5 wherein the polymer is present in an amount of between about 40% and about 95% of the total weight of the solid dispersion.
  14. 14 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the amorphous solid dispersion according to claim 1 .
  15. 15 . The pharmaceutical composition according to claim 14 , wherein said composition is in the form of a solid oral dosage form.
  16. 16 . A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the amorphous solid dispersion according to claim 1 .
  17. 17 . The amorphous solid dispersion according to claim 1 wherein said solid dispersion is prepared by hot-melt extrusion, lyophilization or spray-drying.
  18. 18 . A method of making a solid dispersion according to claim 1 , comprising: a) mixing the compound of Formula I and the polymer in a solvent to provide a feeder solution; and b) spray drying the feeder solution to provide the solid dispersion.
  19. 19 . The method according to claim 18 , wherein the compound of Formula I is provided as either the free base, salt, or solvate.
  20. 20 . The method according to claim 18 , wherein the solvent is selected from acetone, ethanol, methanol, or dichloromethane.

Description

BACKGROUND Field of the Invention The present disclosure relates to pharmaceutical formulations comprising substituted pyrazolopyrimidines. More particularly, this disclosure relates to bioavailable amorphous solid dispersions of substituted pyrazolopyrimidines. This disclosure also relates to processes for preparing these amorphous solid dispersions, pharmaceutical compositions comprising such dispersions, and to methods of use thereof. Background of the Invention Substituted pyrazolopyrimidines, such as 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzyl)-1H-pyrazolo[3,4-d] pyrimidine of Formula (II) and 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzyl)-1H-pyrazolo[3,4-d]pyrimidine of Formula (III) are inhibitors of ubiquitin-specific-processing protease 1 (USP1). U.S. Provisional Patent Appl. No. 62/946,263 discloses compounds of Formula II and Formula III and is herein incorporated by reference in its entirety. It has now been determined that these compounds have limited solubility in aqueous environments at physiological pH and less than optimal bioavailability. Therefore, a need exists for bioavailable formulations of substituted pyrazolopyrimidines compounds which exhibit improved solubility and bioavailability, have a desirable pharmaceutical profile, and are amenable to manufacturing conditions. SUMMARY OF THE DISCLOSURE Accordingly, the present disclosure provides an amorphous solid dispersion, comprising: a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: R is C1-3 alkyl; and X1 and X2 are independently selected from the group consisting of N and C; and a polymer; wherein said compound is in a solid substantially amorphous form and is dispersed in the polymer. In one aspect, the compound is 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzyl)-1H-pyrazolo[3,4-d]pyrimidine of Formula II: or a pharmaceutically acceptable salt, thereof. In another aspect, the compound is 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzyl)-1H-pyrazolo[3,4-d] pyrimidine of Formula (III): or a pharmaceutically acceptable salt, thereof. Another aspect of the present invention provides a method of making the amorphous solid dispersions. Another aspect of the present invention provides an oral dosage form comprising the amorphous solid dispersions disclosed herein. In a further aspect, the present invention relates to methods of treating cancer by administering one of said solid amorphous dispersion, pharmaceutical composition or dosage form to a patient in need thereof. The foregoing and other objectives, features, and advantages of the invention will be more readily understood upon consideration of the following detailed description of the invention, taken in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 shows an X-ray powder diffraction (XRPD) overlay of six amorphous solid dispersions (ASD) of compound of Formula II. FIG. 2(a) shows PLM image of ASD of compound of Formula II dispersed in Eudragit L100-55 with 20% drug loading; 2(b) shows PLM image of ASD of compound of Formula II dispersed in Eudragit L100-55 with 33% drug loading; 2(c) shows PLM image of ASD of compound of Formula II dispersed in Eudragit L100-55 with 50% drug loading; 2(d) shows PLM image of ASD of compound of Formula II dispersed in HPMCAS-HG with 20% drug loading. FIG. 3 shows an XRPD overlay of ASDs of Formula II after 12 days at 40° C./75% RH chamber. FIG. 4 shows an XRPD overlay of the two ASDs of Formula II after suspension in vehicle for 24 hours. FIG. 5 shows a modulated differential scanning calorimetry (mDSC) trace of ASD of Formula II with 33% drug loading dispersed in HPMC-AS. FIG. 6 shows an XRPD pattern of ASD of Formula II with 33% drug loading dispersed in HPMC-AS. FIG. 7 shows a PLM image of ASD sample of Formula II with 33% drug loading dispersed in HPMC-AS. FIG. 8 shows Thermogravimetric analysis (TGA)/mDSC curves of ASD sample of Formula II with 33% drug loading dispersed in HPMCAS-HG. FIG. 9 shows a high performance liquid chromatography (HPLC) trace of sample of Formula II with 33% drug loading dispersed in HPMCAS-HG. FIG. 10 shows XRPD overlay of six ASDs of Formula III. FIG. 11 shows PLM images of ASD of Formula III. FIG. 11 (a) shows PLM image of ASD of Formula III dispersed in Eudragit L100-55 with 20% drug loading; 11(b) shows PLM image of ASD of Formula III dispersed in Eudragit L100-55 with 33% drug loading; 11(c) shows PLM image of ASD of Formula III dispersed in Eudragit L100-55 with 50% drug loading; 11(d) shows PLM image of ASD of Formula III dispersed in HPMCAS-HG with 20% drug loading. FIG. 12 shows XRPD overlay of six ASDs of Formula III after 12 days in 40° C./75% RH. FIG. 13 shows XRPD overlay of ASDs of Formula III after suspension in vehicle