Crystalline RET inhibitors

Abstract

This invention provides a crystalline form of serpercatinib useful for the treatment and prevention of diseases that can be treated with RET kinase inhibitors, such as RET kinase-related diseases and disorders, and a method for producing this crystalline form. [Solution] A method for converting serpercatinib to the thermodynamically stable polymorph B is provided, along with its crystallization. A synthetic route is also provided, which includes reacting one or more intermediate or precursor compounds under conditions effective for producing polymorph B.

Claims

1. The crystalline form of serpercatinib, (a) When measured using an X-ray wavelength of 1.5418 A, the peak at 21.1° and , with one or more peaks at 17.1°, 17.7°, and 19.8°±0.2°2θ, Includes, X-ray powder diffraction (XRPD) patterns, or (b) 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 pp At m (each ±0.2 ppm), the high magnetic resonance of adamantane (δ = 29.5 p) Includes a peak relative to pm. １３ 13C solid-state NMR spectrum, A crystalline form of serpercatinib characterized by at least one of the following.

2. When the crystal morphology is measured using an X-ray wavelength of 1.5418 Å, at 21.1° The peaks are at 7.5°, 12.0°, 13.2°, 17.1°, 17.7° and 19.8°. The X-ray powder diffraction (XRPD) pattern includes one or more peaks at ±0.2°2θ. The crystalline form of serpercatinib according to claim 1, characterized by the following:

3. The aforementioned crystal forms are 7.5°, 10.9°, 12.0°, 13.2°, 17.1°, 17 Special characteristics occurring at 7°, 18.2°, 19.8°, 21.1° and 24.5°±0.2°²θ It is characterized by having an X-ray powder diffraction (XRPD) pattern with a characteristic peak. The crystalline form of serpercatinib as described in item 1.

4. The aforementioned crystal forms are 26.4, 28.0, 42.0, 43.9, 48.0, 56.3, 6 ９．５、８０．４、１０２．３、１０６．８、１１５．２、１２０．８、１３０．２、１ 34.9, 140.6, 149.5, 152.5, and 163.5 ppm (each ±0 At 2 ppm, the high magnetic resonance of adamantane (δ = 29.5 ppm) was used as the reference. Including the peak １３ The cell percatheter according to claim 1, characterized by a 1C solid-state NMR spectrum. The crystalline form of the nib.

5. The aforementioned crystal forms are 26.4, 27.4, 28.0, 42.0, 43.4, 43.9, 4 ８．０、５３．９、５６．３、５８．３、６９．５、７７．９、８０．４、１０２．３、 １０６．８、１１３．６、１１５．２、１１８．２、１２０．８、１２５．２、１３０． ２、１３４．９、１３６．９、１４０．６、１４８．４、１４９．５、１５１．２、１５ At 2.5, 158.2, and 163.5 ppm (each ±0.2 ppm), Includes a peak based on the high magnetic resonance of mantan (δ = 29.5 ppm). １３ C solid NM The crystalline form of serpercatinib according to claim 1, characterized by an R spectrum.

6. The crystalline form of serpercatinib according to any one of claims 1 to 5, and pharmaceutically acceptable A pharmaceutical composition comprising a carrier, diluent, or excipient.

7. The claim states that the composition contains less than about 20% by weight of other crystalline forms of serpercatinib. The pharmaceutical composition described in item 6.

8. The claim states that the composition contains less than about 10% by weight of other crystalline forms of serpercatinib. The pharmaceutical composition described in item 6.

9. The claim states that the composition contains less than about 5% by weight of another crystalline form of serpercatinib. The pharmaceutical composition described in 6.

10. A method for treating cancer in a patient, in an effective amount for a patient who requires such treatment. A method comprising administering serpercatinib according to any one of claims 1 to 9.

11. A pharmaceutical composition according to any one of claims 6 to 9, for use in therapeutic purposes.

12. A pharmaceutical composition according to any one of claims 6 to 9, for use in the treatment of cancer.

13. The aforementioned cancers include lung cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated thyroid carcinoma, and recurrent thyroid cancer. Differential thyroid carcinoma, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (each, M EN2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, nipple Selected from the group consisting of renal cell carcinoma, gastrointestinal mucosal ganglioneuroma, and cervical cancer. A pharmaceutical composition for use according to claim 12.

14. The pharmaceutical composition for use according to claim 13, wherein the cancer is medullary thyroid carcinoma.

15. The aforementioned cancer is lung cancer, and the aforementioned lung cancer is small cell lung cancer, non-small cell lung cancer, or bronchiolar cancer. For use according to claim 13, the lung cell carcinoma, RET-fusion lung cancer, or lung adenocarcinoma Pharmaceutical composition.

16. The pharmaceutical composition for use according to claim 15, wherein the cancer is RET-fusion lung cancer.

17. A process for producing the crystalline form of selpercatinib according to claim 1, (a) Suspending serpercatinib in a solvent, (b) Heat the suspension to 50°C to 60°C while stirring for 30 to 90 minutes, (c) Remove heat and cool the suspension to room temperature to form solid crystals, (d) Recovering the solid crystals A process that includes this.

18. The process according to claim 17, wherein the solvent comprises methanol.

19. The process according to claim 17 or 18, wherein the suspension is heated to 55°C.

20. The suspension is stirred for 60 minutes, according to any one of claims 17 to 19. vinegar.

21. The solid crystal is recovered by vacuum filtration, as described in any one of claims 17 to 20. The loading process.

22. A method for converting serpercatinib form A to serpercatinib form B.

23. The above method converts serpercatinib form A to C １ ~C ５ Combined with alcohol, slender The process includes generating a substance and isolating cell percatinib form B from the slurry. The method according to claim 22.

24. Said C １ ~C ５ The alcohol is at a temperature of approximately 10°C to approximately 30°C, as described in claim 22 or 23. The method.

25. Said C １ ~C ５ The alcohol is at about 15 to 25°C, any one of claims 22 to 24 The method described in section [section number].

26. Said C １ ~C ５ The alcohol is at approximately 20°C, as described in any one of claims 22 to 25. Method of loading.

27. Said C １ ~C ５ The alcohol is at a temperature of approximately 10°C to approximately 80°C, as described in claim 22 or 23. The method.

28. Said C １ ~C ５ The alcohol comprises methanol, in any one of claims 22 to 27. Method of description.

29. C １ ~C ５ Claims 22-2, wherein the alcohol comprises at least 90% by weight of methanol. The method described in any one of item 8.

30. The slurry is stirred for at least about 10 minutes, or otherwise oscillated. The method described in any one of the requests 22 to 29.

31. Isolating form B includes vacuum filtration, according to any one of claims 22 to 30. method.

32. The isolation of morphology B includes centrifugation, according to any one of claims 22 to 31. method.

33. The method described in any one of claims 22 to 32 further comprises drying the serpercatinib form B. Method of loading.

34. The method described above is a. Dissolve the selpercatinib form A in a solvent containing DMSO to form a solution. That thing, b. Adding water to the solution to form a slurry, c. The method according to claim 22, comprising isolating the selpercatinib form B. 。

35. Claim 34, wherein the concentration of form A dissolved in DMSO is approximately 10 to 15 mL / g. Method of description.

36. Claim 34, or This is the method described in 35.

37. Forming the solution in step a is the process for the cerpercatinib form A and the DMS Any of claims 34 to 36, comprising heating a solvent containing O to about 50°C to about 70°C. The method described in item 1.

38. The solution is cooled to a temperature of less than approximately 70°C and more than approximately 20°C, according to claims 34 to 37. The method described in either of the above terms.

39. The method according to claim 37, wherein the solution is cooled to a temperature of about 50°C.

40. Step b involves adding approximately 0.1 to 1 mL of water per gram of form A to the solution. The method according to any one of claims 34 to 39, including the above.

41. Step b includes adding approximately 0.3 mL of water per gram of form A to the solution. The method according to any one of claims 34 to 40.

42. Step b further includes adding a seed crystal of form B in an amount of about 1 to about 15% by weight, claim The method described in any one of items 34 to 41.

43. Step b further includes adding a seed crystal of form B in an amount of about 1 to about 10% by weight, claim The method described in any one of paragraphs 34 to 42.

44. The method according to claim 42 or 43, wherein approximately 5% by weight of seed crystals of form B are added.

45. After the water is added in step b, the slurry is stirred for about 6 to 72 hours. The method according to any one of claims 34 to 44.

46. The slurry is stirred for at least 12 hours, according to any one of claims 34 to 45. Method of description.

47. Claim 3 further comprises adding a second fraction of the amount of water to the slurry as step b. The method described in any one of items 4 to 46.

48. Approximately 0.5 to 3 mL of water per gram of form A is added to the slurry, claim Method 47.

49. The slurry in step b is cooled to approximately 20-30°C, according to any of claims 34-48. The method described in any one of the items.

50. The method according to any one of claims 34 to 49, wherein step c includes filtration.

51. The isolated serpercatinib form B from step c is methanol, ACN, M The method according to any one of claims 34 to 50, wherein the solvent is washed with TBE or water. 。

52. The isolated cerpercatinib form B is washed with a methanol-containing solvent, claim The method described in item 51.

53. Until the isolated serpercatinib form B contains less than 0.5% by weight of DMSO The method according to claim 52, wherein the isolated cell percatinib form B is washed with methanol. 。

54. The above method involves combining serpercatinib form A and methanol to form a slurry. The slurry is stirred until >99% by weight of form A is converted to form B. The method of claim 22, comprising the action of

55. The method according to claim 54, wherein the slurry is stirred for about 18 to 24 hours.

56. The concentration of cerpercatinib form A in the methanol is approximately 8 mL / g, according to the claim. The method described in paragraph 54 or 55.

57. The above method involves dissolving serpercatinib form A in DMSO at approximately 60-80°C, and then morph To form a solution having a DMSO concentration of approximately 10-15 mL / g per gram of A. The solution is cooled to approximately 40-60°C, water is added, and optionally, the resulting mixture is... The process involves sowing seed crystals of form B, stirring the mixture, and then adding water. The process involves heating the mixture to approximately 60-80°C, cooling the mixture, and the The method according to claim 22, comprising isolating morphology B.

58. The method according to claim 57, wherein 5% by weight of seed crystals of form B is added to the mixture.

59. The first addition of water is approximately 0.1 mL / g to approximately 0.5 mL / g of Form A. The method described in claim 57 or 58.

60. The addition of the second water is approximately 1.0 to 1.5 mL / g of form A, according to claims 57 to 59. The method described in either of the above terms.

61. Serpercatinib as polymorph B of formula I, 【Chemistry 1】 or a process for preparing a pharmaceutically acceptable salt thereof, The above process involves a compound having the following structure, 【Chemistry 2】 Alternatively, react the salt thereof with 6-methoxynicotinaldehyde in a solvent in the presence of an acid and a reducing agent. This includes preparing serpercatinib form B or a pharmaceutically acceptable salt thereof. process.

62. The process further comprises preparing a compound of structure [3] or a salt thereof, wherein the process is as follows: Compounds of structure, 【Transformation 3】 or its salt (wherein R １ The amine protecting group is reacted with a deprotecting agent to obtain structure [3] The process according to claim 61, comprising forming a compound or a salt thereof.

63. The aforementioned deprotecting agent is trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid. methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride, aluminum trichloride, and The process according to claim 61 or 62, selected from the group consisting of and boron trifluoride.

64. The deprotective agent is selected from the group consisting of sulfuric acid, p-toluenesulfonic acid, and acetyl chloride. The process according to claim 62 or 63, which is selected.

65. The reducing agent is alkali metal borohydride, hydrazine compound, citric acid, citric acid Select from the group consisting of salts, succinic acid, succinate salts, ascorbic acid, and ascorbate salts. The process according to any one of claims 61 to 64.

66. The reducing agent is sodium triacetoxyborohydride (STAB), sodium borohydride A selection from the group consisting of thorium and sodium borohydride, claims 61 to The process described in any one of paragraphs 65.

67. R １ However, formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carba Mate, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-buty Luoxycarbonyl (Boc), trimethylsilyl, 2-trimethylsilyl-ethanesulfate Honyl, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmeth Luoxycarbonyl, nitroberatryloxycarbonyl, p-methoxybenzyl, and The process according to any one of claims 61 to 66, selected from the group consisting of tosyl.

68. R １ However, the claims 61 to 67 are tert-butyloxycarbonyl (Boc). The process described in either item.

69. The acid is selected from the group consisting of pivalic acid and acetic acid, any one of claims 61 to 68. The process described in item 1.

70. The reaction is carried out in a solvent, and the solvent contains anisole, any one of claims 61 to 69. The process described in item 1.

71. Having structure [3], 4-[6-(3,6-diazabicyclo[3.1.1]heptane- 3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxy-prop A compound that is xy)pyrazolo[1,5-a]pyridine-3-carbonitride, 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

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