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KR-20260066812-A - CRYSTALLINE FORMS OF PYRIMIDINO DIAZEPINE DERIVATIVE

KR20260066812AKR 20260066812 AKR20260066812 AKR 20260066812AKR-20260066812-A

Abstract

The present invention relates to a novel crystalline pyrimidodiazepine derivative exhibiting excellent antitumor activity. Furthermore, the present invention relates to a pharmaceutical composition containing said crystalline form as an active ingredient, and its use in the prevention or treatment of diseases. Additionally, the present invention relates to a method for preparing the crystalline form.

Inventors

  • 스케드 벤자민
  • 노던 줄리안
  • 애서턴 크리스
  • 미키티크 존

Assignees

  • 싸이클라셀 리미티드

Dates

Publication Date
20260512
Application Date
20200814
Priority Date
20190816

Claims (20)

  1. A crystalline form of the following compound (I), which is a pharmaceutically acceptable salt, a solvate of a pharmaceutically acceptable salt, or a co-crystalline form: (I)
  2. In paragraph 1, a crystalline form, which is a hydrochloride, more preferably a monohydrochloride monohydrate.
  3. In Paragraph 2, the following: 5.57 ± 0.2, 6.19 ± 0.2, 7.97 ± 0.2, 8.32 ± 0.2, 10.48 ± 0.2, 10.72 ± 0.2, 11.83 ± 0.2, 12.53 ± 0.2, 12.74 ± 0.2, 13.34 ± 0.2, 13.86 ± 0.2, 14.69 ± 0.2, 15.62 ± 0.2, 16.02 ± 0.2, 16.75 ± 0.2, 17.02 ± 0.2, 17.42 ± 0.2, 18.19 ± 0.2, 18.81 ± 0.2, 19.08 ± 0.2, 19.49 ± 0.2, 19.83 ± 0.2, 20.15 ± 0.2, 20.55 ± 0.2, 21.12 ± 0.2, 22.82 ± 0.2, 23.78 ± 0.2, 24.68 ± 0.2, 25.10 ± 0.2, 25.70 ± 0.2, 25.86 ± 0.2, 26.86 ± 0.2, 27.92 ± 0.2, 28.53 ± 0.2, 28.92 ± 0.2, 29.71 ± 0.2, 30.80 ± 0.2, 31.56 ± 0.2, 32.38 ± 0.2, 32.98 ± 0.2 and 34.13 ± 0.2 A crystalline form characterized by an X-ray powder diffraction pattern having two or more diffraction peaks at a 2θ value selected from.
  4. In Paragraph 2 or 3, the following: A crystalline form characterized by an X-ray powder diffraction pattern including two or more diffraction peaks at 2θ values selected from 8.32 ± 0.2, 10.48 ± 0.2, 11.83 ± 0.2, 12.53 ± 0.2, 16.02 ± 0.2, 16.75 ± 0.2, 18.19 ± 0.2, 18.81 ± 0.2, 19.49 ± 0.2, 20.55 ± 0.2, and 25.70 ± 0.2.
  5. In any one of paragraphs 2 through 4, A crystalline form characterized by an X-ray powder diffraction pattern in which the peak position substantially corresponds to the peak position of the pattern shown in FIG. 25.
  6. A crystalline form according to any one of claims 2 to 5, characterized by a differential scanning calorimeter trace recorded at a heating rate of 20°C per minute exhibiting a maximum endothermic peak at a temperature of about 265°C to about 275°C.
  7. A crystalline form characterized by a differential scanning calorimeter trace substantially consistent with that shown in FIG. 4, in any one of claims 2 to 6.
  8. In paragraph 1, the crystalline form is L-malate.
  9. In claim 8, a crystalline form in which the ratio of L-malate to compound (I) is 2:1.
  10. In Paragraph 8 or 9, the following: 4.48 ± 0.2, 5.57 ± 0.2, 5.89 ± 0.2, 7.64 ± 0.2, 9.02 ± 0.2, 9.95 ± 0.2, 10.20 ± 0.2, 10.90 ± 0.2, 12.20 ± 0.2, 12.81 ± 0.2, 13.47 ± 0.2, 14.15 ± 0.2, 14.69 ± 0.2, 14.95 ± 0.2, 15.67 ± 0.2, 16.06 ± 0.2, 17.91 ± 0.2, 18.56 ± 0.2, 19.25 ± 0.2, 20.15 ± 0.2, 20.65 ± 0.2, 21.35 ± 0.2, 21.94 ± 0.2, 22.85 ± 0.2, 24.07 ± 0.2, 24.28 ± 0.2, 24.98 ± 0.2, 25.63 ± 0.2, 26.82 ± 0.2, 27.70 ± 0.2, 29.25 ± 0.2, 30.24 ± 0.2, 31.28 ± 0.2, 32.16 ± 0.2, 33.03 ± 0.2 and 34.47 ± 0.2 A crystalline form characterized by an X-ray powder diffraction pattern having two or more diffraction peaks at a 2θ value selected from.
  11. In any one of paragraphs 8 through 10, the following: A crystalline form characterized by an X-ray powder diffraction pattern containing two or more diffraction peaks at 2θ values selected from 14.69 ± 0.2, 14.95 ± 0.2, 16.06 ± 0.2, 17.91 ± 0.2, 18.56 ± 0.2, 19.25 ± 0.2, 20.15 ± 0.2, 21.94 ± 0.2, 24.07 ± 0.2, and 24.28 ± 0.2.
  12. In any one of paragraphs 8 through 11, A crystalline form characterized by an X-ray powder diffraction pattern in which the peak position substantially corresponds to the peak position of the pattern shown in FIG. 26.
  13. A crystalline form according to any one of claims 8 to 12, characterized by a differential scanning calorimeter trace recorded at a heating rate of 20°C per minute, showing a maximum endothermic peak at a temperature of about 185°C to about 190°C and a second, broader peak at about 220°C.
  14. In any one of paragraphs 8 through 13, A crystalline form characterized by a differential scanning calorimeter trace substantially consistent with that shown in FIG. 6.
  15. In paragraph 1, the crystalline form, which is succinate.
  16. In paragraph 15, a crystalline form in which the ratio of succinic acid to compound (I) is 2:1.
  17. In Paragraph 15 or 16, the following: 3.16 ± 0.2, 5.47 ± 0.2, 9.01 ± 0.2, 10.10 ± 0.2, 11.45 ± 0.2, 12.12 ± 0.2, 12.94 ± 0.2, 13.17 ± 0.2, 14.19 ± 0.2, 14.43 ± 0.2, 14.67 ± 0.2, 15.08 ± 0.2, 15.51 ± 0.2, 15.69 ± 0.2, 16.76 ± 0.2, 17.55 ± 0.2, 17.69 ± 0.2, 18.54 ± 0.2, 18.95 ± 0.2, 19.52 ± 0.2, 19.84 ± 0.2, 20.30 ± 0.2, 20.45 ± 0.2, 21.04 ± 0.2, 21.36 ± 0.2, 21.83 ± 0.2, 22.12 ± 0.2, 22.76 ± 0.2, 23.11 ± 0.2, 23.44 ± 0.2, 23.96 ± 0.2, 24.60 ± 0.2, 24.98 ± 0.2, 25.21 ± 0.2, 25.44 ± 0.2, 25.61 ± 0.2, 25.83 ± 0.2, 26.18 ± 0.2, 26.57 ± 0.2, 26.89 ± 0.2, 27.36 ± 0.2, 27.72 ± 0.2, 28.63 ± 0.2, 29.23 ± 0.2, 29.99 ± 0.2, 30.44 ± 0.2, 30.66 ± 0.2, 31.36 ± 0.2, 31.99 ± 0.2, 32.33 ± 0.2, 32.77 ± 0.2, 33.11 ± 0.2, 33.53 ± 0.2, 34.05 ± 0.2 and 34.50 ± 0.2 A crystalline form characterized by an X-ray powder diffraction pattern having two or more diffraction peaks at a 2θ value selected from.
  18. In any one of paragraphs 15 through 17, A crystalline form characterized by an X-ray powder diffraction pattern containing two or more diffraction peaks at 2θ values selected from 10.10 ± 0.2, 14.67 ± 0.2, 15.08 ± 0.2, 15.51 ± 0.2, 15.69 ± 0.2, 17.55 ± 0.2, 18.54 ± 0.2, 18.94 ± 0.2, 19.52 ± 0.2, and 21.83 ± 0.2.
  19. In any one of paragraphs 15 through 18, A crystalline form characterized by an X-ray powder diffraction pattern in which the peak position substantially corresponds to the peak position of the pattern shown in FIG. 27.
  20. In any one of paragraphs 15 through 19, A crystalline form characterized by a differential scanning calorimeter trace recorded at a heating rate of 20°C per minute exhibiting a maximum endothermic peak at a temperature of approximately 185°C to approximately 190°C.

Description

Crystalline Forms of Pyrimidino Diazepine Derivatives The present invention relates to a crystalline form (crystalline form) of a pyrimido-diazepine derivative. Furthermore, the present invention relates to a pharmaceutical composition containing said crystalline form as an active ingredient, and its use in the prevention or treatment of diseases. Additionally, the present invention relates to a method for preparing said crystalline form. Polo-like kinases are a family of serine threonine kinases that are important regulators of cell cycle progression and DNA damage response (Petronczki et al, Curr Opin Cell Biol. 2008. 12. 20(6):650-60). PLK1 is frequently overexpressed in cancer, and its levels correlate with aggressiveness and have prognostic value in predicting outcomes (Kanaji et al. Oncology. 2006; 70(2):126-33). Cancer cell proliferation is blocked in vitro and in vivo by small molecule PLK1 inhibitors and PLK1 antisense/siRNA ( Spankuch et al, Oncogene, 2007. 26(39):5793-807). PLK1 inhibitors induce mitotic arrest and subsequent apoptosis. Due to the central role of PLK1 in mitosis and cell division, rapidly proliferating normal cells are also affected by PLK1 inhibitors. Consequently, clinical PLK1 inhibitors have been shown to have a narrow therapeutic range and cause significant hematological toxicity (Schoffski et al, Eur J Cancer, 2012 Jan; 48(2):179-86). Identifying patient/tumor selection markers and therapeutic regimens to expand the therapeutic range is crucial for the successful development of these agents. The TP53 mutation has been shown to be one of these predictive markers for sensitivity to PLK1 inhibitors (Degenhardt et al, Clin Cancer Res. 2010 Jan 15; 16(2):384-9). Small molecule benzthiazole-3-oxide PLK1 inhibitors and their use in the treatment of proliferative disorders are described in International Patent Application WO 2004/067000 under the name of Cyclacel Limited. Furthermore, a series of pyrimido-diazepinone molecules have been shown to potently and selectively inhibit PLK1 (see International Patent Application WO 2009/040556; Cyclacel Limited), and have demonstrated potent antiproliferative activity invitro and in vivo. A compound known as 4-((9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro-[cyclopropane-1,7'-pyrimido][4,5-b][1,4]diazepine]-2'-yl)amino)-3-methoxy-N-((trans)-4-(4-methylpiperazine-1-yl)cyclohexyl)benzamide or 4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[4,5-b][1,4]diazepine]-2'-ylamino)-N((trans)-4-(4-methylpiperazine-1-yl)cyclohexyl)-3-methoxybenzamide (I) was first disclosed in WO 2009/040556 and has the following structure: (I) According to research, compound (I) is a potent inhibitor of polo-like kinase 1 (PLK1) and is therefore therapeutically useful for the treatment of various proliferative disorders (including but not limited to cancer, leukemia, lymphoma, glomerulonephritis, rheumatoid arthritis and psoriasis), immune-mediated and inflammatory disorders, autoimmune and autoimmune-mediated disorders, renal disorders and viral disorders. Different solid forms (including solvated forms) of active pharmaceutical ingredients may possess different properties. Such variations in the properties of different solid-state forms and solvates can provide a basis for improving formulations by, for example, promoting better processing or handling characteristics, improving solubility profiles, or enhancing stability (as well as polymorphism) and storage stability. These variations in the properties of different solid forms can also provide improvements to the final dosage form, for example, if they serve to improve bioavailability. Different solid forms and solvates of active pharmaceutical ingredients can also generate various polymorphs or crystalline forms, which may provide additional opportunities to utilize variations in the properties of the solid active pharmaceutical ingredient to deliver improved products. By discovering new solid forms and solvates of pharmaceuticals, it is possible to provide materials with desirable processing characteristics, such as ease of handling, ease of processing, storage stability, and ease of purification, or desirable intermediate crystalline forms that facilitate conversion to other polymorphic forms. New polymorphs and solvates of pharmaceutically useful compounds can also provide opportunities to improve the performance characteristics (solubility profile, bioavailability, etc.) of pharmaceutical products. This expands the repertoire of materials that formulation scientists can use for formulation optimization by providing products with various characteristics, such as different crystal moisture, higher crystallinity, or polymorphic stability, which can provide, for example, better processing or handling characteristics, an improved solubility profile, or an enhanced shelf life. At least for this reason, different solid state forms of compound (I) are required. Th