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US-12617767-B2 - Crystalline forms of somatostatin modulators

US12617767B2US 12617767 B2US12617767 B2US 12617767B2US-12617767-B2

Abstract

Described herein are pharmaceutically acceptable salts of a somatostatin modulator, crystalline forms of the pharmaceutically acceptable salts of the somatostatin modulator, methods of making such salts and crystalline forms, pharmaceutical compositions and medicaments comprising such salts and crystalline forms, and methods of using such salts and crystalline forms in the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.

Inventors

  • Jayachandra P. REDDY
  • Yuxin Zhao
  • Mahmoud Mirmehrabi
  • Alex MAYO
  • Madhukar KOTA
  • Uttam DASH
  • Vijaykumar Umesh NAIK
  • Praveen Kumar Bandaru
  • Yuanqing Fang

Assignees

  • Crinetics Pharmaceuticals, Inc.

Dates

Publication Date
20260505
Application Date
20200715

Claims (16)

  1. 1 . A mesylate salt of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile, or solvate thereof, wherein the mesylate salt is: an amorphous form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having: a modulated Differential Scanning calorimetry thermogram with a glass transition temperature having an onset at about 166.6° C. and a midpoint at about 169.3° C.; a Thermogravimetric Analysis pattern with a 3.85% w/w loss between 4° and 170° C.; or a combination thereof; a crystalline hydrate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluornphenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 7.10° 2-Theta, about 17.44° 2-Theta, about 22.18° 2-Theta, and about 25.20° 2-Theta as measured using Cu Kal radiation; a crystalline isopropyl solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 6.10° 2-Theta, about 6.70° 2-Theta, about 17.75° 2-Theta, and about 22.22° 2-Theta as measured using Cu Kα1 radiation; a crystalline tetrahydrofuran solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 6.42° 2-Theta, about 19.99° 2-Theta, and about 21.12° 2-Theta as measured using Cu Kα1 radiation; a crystalline methyl isobutyl ketone solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 5.63 ° 2-Theta, about 6.27° 2-Theta, about 20.55° 2-Theta, and about 22.33 ° 2-Theta as measured using Cu Kα1 radiation; a crystalline ethyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 6.62° 2-Theta, about 13.21° 2-Theta, about 19.79 ° 2-Theta, and about 21.72° 2-Theta as measured using Cu Kα1 radiation; a crystalline isopropyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 5.66° 2-Theta, about 16.77° 2-Theta, and about 22.78° 2-Theta as measured using Cu Kal radiation; crystalline 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 6.32° 2-Theta, about 6.72° 2-Theta about 12.33° 2-Theta, and about 21.47 ° 2-Theta as measured using Cu Kal radiation; crystalline 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 5.42° 2-Theta, about 15.90° 2-Theta about 19.59° 2-Theta, and about 21 52° 2-Theta as measured using Cu Kal radiation; a crystalline acetone solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 5.67 ° 2-Theta, about 14.63 ° 2-Theta, about 22.14° 2-Theta, and about 24.91 ° 2-Theta as measured using Cu Kα1 radiation; a crystalline acetonitrile solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 5.18° 2-Theta, and about 17.21° 2-Theta as measured using Cu Kα1 radiation; a crystalline hydrate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 5.56° 2-Theta, 15.87° 2-Theta, 18.43 ° 2-Theta, and about 24.80° 2-Theta as measured using Cu Kα1 radiation; or crystalline 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 6.97 ° 2-Theta, about 17.26° 2-Theta, about 19.33° 2-Theta, and about 20.94 ° 2-Theta as measured using Cu Kal radiation.
  2. 2 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is an amorphous form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having: a modulated Differential Scanning calorimetry thermogram with a glass transition temperature having an onset at about 166.6° C. and a midpoint at about 169.3° C.; a Thermogravimetric Analysis pattern with a 3.85% w/w loss between 4° and 170° C.; or a combination thereof.
  3. 3 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is a crystalline hydrate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluornphenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having: an XRPD pattern with X-ray diffraction pattern reflections at about 7.10° 2-Theta, about 17.44° 2-Theta, about 22.18° 2-Theta, and about 25.20° 2-Theta as measured using Cu Kα1 radiation; and is further characterized as having: a Differential Scanning calorimetry thermogram with an exothermic event having an onset at about 192.8° C. and a peak at about 213.3° C.; an endothermic event having an onset at about 252.2° C. and a peak at about 272.3° C.; and an endothermic event having an onset at about 296.6° C. and a peak at about 298.9° C.; a Thermogravimetric Analysis pattern with a 0.12% w/w loss from 40 to 140° C. and a further 0.62% w/w loss from 140 to 290° C.; or a combination thereof.
  4. 4 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is a crystalline isopropyl solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 6.10° 2-Theta, about 6.70° 2-Theta, about 17.75° 2-Theta, and about 22.22° 2-Theta as measured using Cu Kα1 radiation.
  5. 5 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is a crystalline tetrahydrofuran solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 6.42° 2-Theta, about 19.99° 2-Theta, and about 21.12° 2-Theta as measured using Cu Kα1 radiation.
  6. 6 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is a crystalline methyl isobutyl ketone solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 5.63° 2-Theta, about 6.27° 2-Theta, about 20.55° 2-Theta, and about 22.33° 2-Theta as measured using Cu Kα1 radiation.
  7. 7 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is a crystalline ethyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 6.62° 2-Theta, about 13.21° 2-Theta, about 19.79° 2-Theta, and about 21.72° 2-Theta as measured using Cu Kα1 radiation.
  8. 8 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is a crystalline isopropyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 5.66° 2-Theta, about 16.77° 2-Theta, and about 22.78° 2-Theta as measured using Cu Kal radiation.
  9. 9 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is crystalline 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 6.32° 2-Theta, about 6.72° 2-Theta, about 12.33° 2-Theta, and about 21.47° 2-Theta as measured using Cu Kα1 radiation.
  10. 10 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is crystalline 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having: an XRPD pattern with X-ray diffraction pattern reflections at about 5.42° 2-Theta, about 15.90° 2-Theta, about 19.59° 2-Theta, and about 21 52° 2-Theta as measured using Cu Kα1 radiation; and is further characterized as having: a Differential Scanning calorimetry thermogram with an endothermic event having an onset at about 254.1° C. and a peak at about 271.9° C.; and an endothermic event having an onset at about 294.5° C. and a peak at about 297.7° C.; a Thermogravimetric Analysis pattern with a 0.1% w/w loss from 40 to 190° C. and a further 0.69% w/w loss from 190 to 310° C.; or a combination thereof.
  11. 11 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is a crystalline acetone solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 5.67° 2-Theta, about 14.63° 2-Theta, about 22.14° 2-Theta, and about 24.91° 2-Theta as measured using Cu Kα1 radiation.
  12. 12 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is a crystalline acetonitrile solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having: an XRPD pattern with X-ray diffraction pattern reflections at about 5.18° 2-Theta, and about 17.21° 2-Theta as measured using Cu Kα1 radiation; and is further characterized as having: a Differential Scanning calorimetry thermogram with an endothermic event having an onset at about 132.6° C. and a peak at about 144.0° C.; an endothermic event having an onset at about 179.7° C. and a peak at about 193.5° C.; and an endothermic event having an onset at about 192.4° C. and a peak at about 211.1° C.; a Thermogravimetric Analysis pattern with a 5.44% w/w loss from 40 to 220° C.; or a combination thereof.
  13. 13 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is a crystalline hydrate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having: an XRPD pattern with X-ray diffraction pattern reflections at about 5.56° 2-Theta, 15.87 °2-Theta, 18.43 ° 2-Theta, and about 24.80° 2-Theta as measured using Cu Kα1 radiation; and is further characterized as having: a Differential Scanning calorimetry thermogram with an endothermic event having an onset at about 206.9° C. and a peak at about 217.6° C.; a Thermogravimetric Analysis pattern with a 4.54% w/w loss from 40 to 260° C.; or a combination thereof.
  14. 14 . The mesylate salt of claim 1 , or solvate thereof, wherein the mesylate salt is crystalline 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl) quinolin-6-yl)-2-hydroxybenzonitrile dimesylate and is characterized as having an XRPD pattern with X-ray diffraction pattern reflections at about 6.97 ° 2-Theta, about 17.26° 2-Theta, about 19.33° 2-Theta, and about 20.94° 2-Theta as measured using Cu Kα1 radiation.
  15. 15 . A pharmaceutical composition comprising the mesylate salt of claim 1 , or a solvate thereof, and at least one pharmaceutically acceptable excipient.
  16. 16 . A method of treating a disease or condition in a mammal comprising administering a mesylate salt of claim 1 , or solvate thereof, to the mammal in need thereof, wherein the disease or condition is acromegaly, a neuroendocrine tumor, an ophthalmic disease or condition, neuropathy, nephropathy, a respiratory disease or condition, cancer, pain, a neurodegenerative disease or condition, an inflammatory disease or condition, a psychiatric disease or condition, or combinations thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of U.S. Provisional Patent Application No. 62/875,285, filed on Jul. 17, 2019, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity. BACKGROUND OF THE INVENTION Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Six subtype somatostatin receptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5) and are encoded by five different somatostatin receptor genes. Modulation of a particular subtype somatostatin receptor, or combination thereof, is attractive for the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity. SUMMARY OF THE INVENTION Disclosed herein is a compound that is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In one aspect disclosed herein, the compound is the amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, the amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction (XRPD) pattern showing a lack of crystallinity; a modulated Differential Scanning Calorimetry thermogram substantially the same as shown in FIG. 1; a modulated Differential Scanning Calorimetry thermogram with a glass transition temperature having an onset at about 166.6° C. and a midpoint at about 169.3° C.; a Thermogravimetric Analysis pattern substantially the same as shown in FIG. 12; a Thermogravimetric Analysis pattern with a 3.85% w/w loss between 40 and 170° C.; or a combination thereof. In another aspect disclosed herein, the compound is a crystalline form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments disclosed herein, the compound is the crystalline Pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, the crystalline Pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in FIG. 3; an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 6.20° 2-Theta, about 6.76° 2-Theta, about 17.14° 2-Theta, and about 21.70° 2-Theta; a Differential Scanning Calorimetry thermogram substantially the same as shown in FIG. 4; a Differential Scanning Calorimetry thermogram with four endothermic events having: an onset at about 78.4° C. and a peak at about 81.8° C.; an onset at about 266.1° C. and a peak at about 270.1° C.; an onset at about 281.1° C. and a peak at about 286.1° C.; and an onset at about 294.6° C. and a peak at about 297.7° C.; a Thermogravimetric Analysis pattern substantially the same as shown in FIG. 5a; a Thermogravimetric Analysis pattern with a 2.28% w/w loss from 60 to 180° C.; a Dynamic Vapour Sorption isotherm plot substantially the same as shown in FIG. 6; a reversible water uptake (9.8% w/w) between 2% and 95% Relative Humidity (RH); an XRPD that converts to Pattern B on storage at 75% RH and 40° C. for 7 days; an XRPD that converts to Pattern B on storage at 96% RH and 25° C. for 3 days; an unchanged XRPD after drying under dynamic vacuum at 50° C. for 2 hours; an XRPD that converts to Pattern P after heating to 255° C.; a 1.5% w/w water content; or a combination thereof. In some embodiments disclosed herein, the compound is the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in FIG. 7; an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 5.58° 2-Theta, about 7.48° 2-Theta, about 15.94° 2-Theta, and about 25.13° 2-Theta; a Differential Scanning Calorimetry thermogram substantially the same as shown in: FIG. 8; or FIG. 10b; a Differential Scanning Calorimetry thermogram with: a broad endothermic event having an onset at about 86.3° C. and a peak at about 115.1° C.; and a