Processing

Please wait...

Settings

Settings

Goto Application

1. WO2016138458 - CRYSTALLINE FORMS OF A PYRROLOPYRIDINE COMPOUND

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

WHAT IS CLAIMED IS:

1. A crystalline form of a compound selected from:

(i?)-N-(4-(3-aminopiperidin-l -yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide ;

and pharmaceutically acceptable salts, solvates, and hydrates thereof.

2. The crystalline form of claim 1, wherein the compound is selected from:

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 - yl)cyclopropanecarboxamide acetic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5-bromo- lH-pyrrolo[2,3-b]pyridin-3 - yl)cyclopropanecarboxamide ethanedisulfonic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5-bromo- lH-pyrrolo[2,3-b]pyridin-3 - yl)cyclopropanecarboxamide fumaric acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5-bromo- lH-pyrrolo[2,3-b]pyridin-3 - yl)cyclopropanecarboxamide ;

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide di-methanesulfonic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 - yl)cyclopropanecarboxamide di-ethanesulfonic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 - yl)cyclopropanecarboxamide mono-methanesulfonic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 - yl)cyclopropanecarboxamide mono -ethane sulfonic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 - yl)cyclopropanecarboxamide di-benzenesulfonic acid salt;

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide di-toluenesulfonic acid salt;

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide maleic acid salt;

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide HBr salt methanol solvate;

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide di-HCl salt; and

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide di-HBr salt;

and pharmaceutically acceptable solvates and hydrates thereof.

3. The crystalline form of claim 1, wherein the compound is selected from:

(i?)-N-(4-(3-aminopiperidin-l -yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide acetic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 - yl)cyclopropanecarboxamide ethanedisulfonic acid salt hydrate;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 - yl)cyclopropanecarboxamide fumaric acid salt hydrate;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5-bromo- lH-pyrrolo[2,3-b]pyridin-3 - yl)cyclopropanecarboxamide ;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5-bromo- lH-pyrrolo[2,3-b]pyridin-3 - yl)cyclopropanecarboxamide cyclopropyl methyl ether solvate;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5-bromo- lH-pyrrolo[2,3-b]pyridin-3 - yl)cyclopropanecarboxamide 1,2-dichloroethane solvate;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 - yl)cyclopropanecarboxamide 2-methyltetrahydrofuran solvate;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 - yl)cyclopropanecarboxamide 1-pentanol solvate;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 - yl)cyclopropanecarboxamide pyridine solvate;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 - yl)cyclopropanecarboxamide 1,4-dioxane solvate;

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide 2-butanol solvate;

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide anisole solvate;

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide 1-propanol solvate;

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide bis-ethanol solvate;

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide bis-methanol solvate;

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide methyl fert-butyl ether solvate;

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide toluene solvate;

(i?)-N-(4-(3-aminopiperidin-l -yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide butyronitrile solvate;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 -yl)cyclopropanecarboxamide di-methanesulfonic acid salt hydrate;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 -yl)cyclopropanecarboxamide di-ethanesulfonic acid salt hydrate;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5-bromo- lH-pyrrolo[2,3-b]pyridin-3 -yl)cyclopropanecarboxamide mono-methanesulfonic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5-bromo- lH-pyrrolo[2,3-b]pyridin-3 -yl)cyclopropanecarboxamide mono -ethane sulfonic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5-bromo- lH-pyrrolo[2,3-b]pyridin-3 -yl)cyclopropanecarboxamide di-benzenesulfonic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 -yl)cyclopropanecarboxamide di-toluenesulfonic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 -yl)cyclopropanecarboxamide di-ethanesulfonic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 -yl)cyclopropanecarboxamide maleic acid salt;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 -yl)cyclopropanecarboxamide HBr salt methanol solvate;

(i?)-N-(4-(3 -aminopiperidin- 1 -yl)-5 -bromo- lH-pyrrolo [2,3 -b]pyridin-3 -yl)cyclopropanecarboxamide di-HCl salt; and

(i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HBr salt.

The crystalline form of claim 1, wherein the compound is (i?)-N-(4-(3-aminopiperidin-l -yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide.

The crystalline form of claim 4, having an X-ray powder diffraction pattern comprising a peak, in terms of °2Θ, at about 12.1.

The crystalline form of claim 4, having an X-ray powder diffraction pattern comprising peak in terms of °2Θ, at about 12.1, 19.9, and 19.5.

The crystalline form of claim 4, having an X-ray powder diffraction pattern comprising peak in terms of °2Θ, at about 12.1, 19.9, 19.5, 23.4, and 24.4.

8. The crystalline form of claim 4, having an X-ray powder diffraction pattern comprising peaks, in terms of °2Θ, at about 12.1, 19.9, 19.5, 23.4, 24.4, 9.7, and 29.4.

9. The crystalline form of claim 4, having an X-ray powder diffraction pattern comprising peaks, in terms of °2Θ, at about 9.7, 12.1, 16.1, 19.5, 19.9, 21.7, 23.4, 24.4, 27.0, 29.4, and 32.2.

10. The crystalline form of claim 4, having X-ray powder diffraction pattern substantially as shown in Figure 4.

1 1. The crystalline form of any one of claims 4 to 10, having a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 258 °C and about 278 °C.

12. The crystalline form of any one of claims 4 to 10, having a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 268 °C.

13. The crystalline form of any one of claims 4 to 10, having a differential scanning calorimetry thermogram substantially as shown in Figure 5.

14. The crystalline form of any one of claims 4 to 13, having a thermogravimetric analysis profile substantially as shown in Figure 5.

15. The crystalline form of claim 4, having an X-ray powder diffraction pattern comprising a peak, in terms of °2Θ, at about 24.3.

16. The crystalline form of claim 4, having an X-ray powder diffraction pattern comprising peaks, in terms of °2Θ, at about 24.3, 20.0, and 13.6.

17. The crystalline form of claim 4, having an X-ray powder diffraction pattern comprising peaks, in terms of °2Θ, at about 24.3, 20.0, 13.6, 23.1, and 18.4.

18. The crystalline form of claim 4, having an X-ray powder diffraction pattern comprising peaks, in terms of °2Θ, at about 24.3, 20.0, 13.6, 23.1, 18.4, 31.8, and 27.3.

19. The crystalline form of claim 4, having an X-ray powder diffraction pattern comprising peaks, in terms of °2Θ, at about 9.1, 13.6, 18.4, 18.8, 20.0, 20.9, 23.1, 24.3, 27.3, 28.8, and 31.8.

20. The crystalline form of any one of claims 4, having an X-ray powder diffraction pattern substantially as shown in Figure 6.

21. The crystalline form of any one of claims 15 to 20, having a differential scanning calorimetry thermogram comprising an endotherm with a peak between about 225 °C and about 245 °C.

22. The crystalline form of any one of claims 15 to 20, having a differential scanning calorimetry thermogram comprising an endotherm with a peak at about 235 °C.

23. The crystalline form of any one of claims 15 to 20, having a differential scanning calorimetry thermogram substantially as shown in Figure 7.

24. A composition comprising a crystalline form of any one of claims 1 to 23, and a solvent selected from: cyclopropyl methyl ether, 1-pentanol, 2-butanol, anisole, 1-propanol, ethanol, methanol, and methyl fert-butyl ether.

25. A pharmaceutical formulation comprising a crystalline form of any one of claims 1 to 23 or a composition of claim 24.

26. The formulation of claim 25, further comprising a DNA damaging agent.

27. The formulation of claim 26, wherein the DNA damaging agent is selected from:

gemcitabine, irinotecan, temozolomide, capecitabine, camptothecin, cisplatin, ara-C, and 5- FU.

28. The formulation of any one of claims 25 to 27, further comprising an excipient.

29. The formulation of claim 28, wherein the formulation is a tablet for oral delivery.

30. A method of treating a disease or disorder modulated by CHK1, comprising administering a crystalline form of any one of claims 1 to 23, or pharmaceutical formulation thereof, to a patient in need thereof.

31. The method of claim 30, wherein the disease is cancer.

32. The method of claim 31, wherein the cancer is selected from: leukemia, pancreatic cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, a refractory solid tumor, and lymphoma.

33. The method of claim 31 or 32, wherein a DNA damaging agent is also administered.

34. The method of claim 33, wherein the DNA damaging agent is selected from: gemcitabine, irinotecan, temozolomide, capecitabine, camptothecin, cisplatin, ara-C, and 5-FU.

35. Use of a crystalline form of any one of claims 1 to 23, in the manufacture of a medicament for treating a disease or disorder modulated by CHK1.

36. The use of claim 35, wherein the disease is cancer.

37. The use of claim 36, wherein the cancer is selected from: leukemia, pancreatic cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, a refractory solid tumor, and lymphoma.

38. The use of claim 36 or 37, wherein the medicament further comprises a DNA damaging

agent.

39. The use claim 38, wherein the DNA damaging agent is selected from: gemcitabine,

irinotecan, temozolomide, capecitabine, camptothecin, cisplatin, ara-C, and 5-FU.

40. The crystalline form of any one of claims 1 to 23, or pharmaceutical formulation thereof, for use in a method of treatment of the human or animal body by therapy.

41. The crystalline form of any one of claims 1 to 23, or pharmaceutical formulation thereof, for use in a method of treating a disease or disorder modulated by CHK1.

42. The crystalline form of claim 41, wherein the disease or disorder is cancer.

43. The crystalline form of claim 42, wherein the cancer is selected from: leukemia, pancreatic cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, a refractory solid tumor, and lymphoma.

44. The crystalline form of claim 42 or 43, for use in combination with a DNA damaging agent.

5. The crystalline form of claim 44, wherein the DNA damaging agent is selected from: gemcitabine, irinotecan, temozolomide, capecitabine, camptothecin, cisplatin, ara-C, and 5- FU.