IP Library › Granted Patent US 12,617,767
Granted Patent B2
US 12,617,767 · App. 17/626,777 · Granted May 5, 2026

Crystalline forms of somatostatin modulators

Inventors: Jayachandra P. Reddy (San Diego, CA); Yuxin Zhao (San Diego, CA); Mahmoud Mirmehrabi (Halifax, CA); Alex Mayo (Halifax, CA); Madhukar Kota (San Diego, CA); Uttam Dash (San Diego, CA); Vijaykumar Umesh Naik (San Diego, CA); Praveen Kumar Bandaru (San Diego, CA); Yuanqing Fang (San Diego, CA)
Assignee: CRINETICS PHARMACEUTICALS, INC.
C07D401/04C07B2200/13
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Quick Facts
Patent No.
US 12,617,767
App. No.
17/626,777
Granted
May 5, 2026
Kind
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.

Claims (52)

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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . A pharmaceutical composition comprising the mesylate salt of claim 1 , or a solvate thereof, and at least one pharmaceutically acceptable excipient.

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.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 10, 2023
From: REDDY, JAYACHANDRA P.; ZHAO, YUXIN; MIRMEHRABI, MAHMOUD; MAYO, ALEX; KOTA, MADHUKAR; DASH, UTTAM; NAIK, VIJAYKUMAR UMESH; BANDARU, PRAVEEN KUMAR; FANG, YUANQING
To: CRINETICS PHARMACEUTICALS, INC.
Reel/Frame 062945/0471 →
Continuity (2)
Provisional Application 62875285 · Jul 17, 2019
Related Publication 20220267295A1 · Aug 25, 2022
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