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EP-4741387-A1 - CRYSTAL FORM OF BIPYRIMIDINE COMPOUND, PREPARATION METHOD THEREFOR AND USE THEREOF

EP4741387A1EP 4741387 A1EP4741387 A1EP 4741387A1EP-4741387-A1

Abstract

The present invention relates to a crystal form of a bipyrimidine compound and a preparation method therefor and a use thereof. In particular, the present invention relates to a crystal form I of 4'-cyclopropyl-5,6'-dimethoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclic[2.2.2]oct-1-yl)methyl)-[2,5'-bipyrimidine]-4-amine, and the X-ray powder diffraction pattern of the crystal form I comprises characteristic peaks at diffraction angles (2θ) of 6.378±0.2°, 9.521±0.2°, 15.721±0.2°, 16.379±0.2°, 16.981±0.2°, 17.560±0.2°, 19.080±0.2°, and 22.200±0.2°. The crystal form I has high stability, high solubility, high plasma concentration, high bioavailability, and excellent pharmacological action, and is therefore suitable for pharmaceutical preparations.

Inventors

  • ZHOU, Lanping
  • GUO, YUSHEN
  • QIU, JUN
  • WU, Maojiang

Assignees

  • Jiangsu Yahong Meditech Co., Ltd.
  • Asieris Pharmaceuticals (Shanghai) Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240701

Claims (12)

  1. Crystal form I of 4'-cyclopropyl-5,6'-dimethoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-[2,5'-bipyrimidin]-4-amine, characterized in that the X-ray powder diffraction pattern thereof comprises characteristic peaks at diffraction angles (2θ) of 6.378±0.2°, 9.521±0.2°, 15.721±0.2°, 16.379±0.2°, 16.981±0.2°, 17.560±0.2°, 19.080±0.2° and 22.200±0.2°.
  2. The crystal form I according to claim 1, characterized in that the X-ray powder diffraction pattern thereof further comprises at least one characteristic peak at diffraction angles (2θ) of 11.938±0.2°, 23.761±0.2°, 25.101±0.2° and 28.700±0.2°.
  3. The crystal form I according to claim 1 or 2, characterized in that the X-ray powder diffraction pattern thereof comprises characteristic peaks at diffraction angles (2θ) of 6.378±0.2°, 9.521±0.2°, 11.938±0.2°, 15.721±0.2°, 16.379±0.2°, 16.981±0.2°, 17.560±0.2°, 19.080±0.2°, 22.200±0.2°, 23.761±0.2°, 25.101±0.2° and 28.700±0.2°.
  4. The crystal form I according to any one of claims 1 to 3, characterized in that the X-ray powder diffraction pattern thereof further comprises at least one characteristic peak at diffraction angles (2θ) of 10.239+0.2°, 12.400+0.2°, 14.882+0.2°, 20.420+0.2° and 25.980+0.2°.
  5. The crystal form I according to any one of claims 1 to 4, characterized in that the X-ray powder diffraction pattern thereof comprises characteristic peaks at diffraction angles (2θ) of 6.378+0.2°, 9.521+0.2°, 10.239+0.2°, 11.938+0.2°, 12.400+0.2°, 14.882±0.2°, 15.721±0.2°, 16.379±0.2°, 16.981±0.2°, 17.560±0.2°, 19.080±0.2°, 20.420±0.2°, 22.200±0.2°, 23.761±0.2°, 25.101±0.2°, 25.980±0.2° and 28.700±0.2°.
  6. The crystal form I according to any one of claims 1 to 5, characterized in that the DSC spectrum thereof shows one endothermic peak at 219.25±2°C.
  7. The crystal form I according to any one of claims 1 to 6, characterized in that the TGA spectrum thereof shows a weight loss of 0.10% from 20°C to 120°C, and a weight loss of 0.37% from 120°C to 250°C.
  8. A method for preparing the crystal form I according to any one of claims 1 to 7, comprising the following steps of: mixing 4'-cyclopropyl-5,6'-dimethoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-[2,5'-bipyrimidin]-4-amine and an organic solvent, and collecting a solid after solid-liquid separation of the resulting suspension; the organic solvent is one or more selected from the group consisting of petroleum ether, C 4 -C 6 ether and C 2 -C 6 nitrile.
  9. The method according to claim 8, comprising the following steps of: triturating 4'-cyclopropyl-5,6'-dimethoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-[2,5'-bipyrimidin]-4-amine in an organic solvent at 0 to 30°C for 10 minutes to 2 hours, and preferably at 25°C for 30 minutes, collecting a solid after solid-liquid separation of the resulting suspension, and optionally drying the solid; the organic solvent is one or more selected from the group consisting of petroleum ether, methyl tert- butyl ether, tetrahydrofuran and acetonitrile, and preferably a mixture of petroleum ether and methyl tert- butyl ether; advantageously, the ratio (w/v) of 4'-cyclopropyl-5,6'-dimethoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-[2,5'-bipyrimidin]-4-amine to the organic solvent is 1:5 to 1:1, and preferably 1:3.
  10. A pharmaceutical composition, comprising the crystal form I according to any one of claims 1 to 7 and one or more pharmaceutically acceptable carrier(s).
  11. A use of the crystal form I according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating or preventing diseases or conditions associated with inhibition of ubiquitin-specific protease 1 (USP1).
  12. A use of the crystal form I according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating or preventing cancer, in particular, the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer.

Description

FIELD OF THE INVENTION The present invention relates to a crystal form of bipyrimidine compound, a method for preparing the same and a use thereof. BACKGROUND OF THE INVENTION Ubiquitination, as a dynamic and reversible process, involves a family of deubiquitinases (DUBs). There are approximately 100 DUBs in a human, which can be divided into a cysteine protease family and a metalloproteinase family. Among them, the cysteine protease family mainly includes ubiquitin-specific proteases (USPs), ubiquitin carboxy-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs), MINDY proteases (MINDYs), and ovarian tumor domain proteases (OTUs). The USPs family is the one representing the greatest quantity among known deubiquitinases, with over 50 types encoded by human genes. It plays a role in various physiological functions such as cell cycle, signal transduction, DNA damage repair, chromosome translocation, and gene transcription, by regulating protease substrates. USP1 belongs to the USP subfamily of DUBs and does not exhibit significant activity on its own. However, it obtains complete enzymatic activity by binding to UAF1 to form a heterodimer complex (USP1/UAF1), and may regulate cellular targets in multiple pathways associated with cancer. For example, the USP1/UAF1 complex enables to deubiquitinate proliferating cell nuclear antigen (PCNA) mono-ubiquitinated by a key protein during translesion synthesis (TLS), to prevent excessive repair thereof, and enables to deubiquitinate fanconi anemia complementation group D2 (FANCD2) mono-ubiquitinated by a key protein in the fanconi anemia (FA) pathway, to prevent improper TLS repair in cells, thereby ensuring genomic stability, etc. These two DNA damage response (DDR) pathways are critical pathways for repairing DNA damage induced by a DNA crosslinker such as cisplatin, mitomycin, and ultraviolet radiation. USP1 can also interact with ID proteins and so on, so as to stabilize their expression in cells through deubiquitination. For example, in osteosarcoma cells, USP1 can deubiquitinate ID1, ID2, and ID3 to promote cell proliferation, and inhibition of USP1 can increase the sensitivity of osteosarcoma cells to chemotherapy. In addition, there are studies to demonstrate that USP1 is closely related to development of resistance to various drugs for tumor treatment. For example, in non-small cell lung cancer (NSCLC) cells with the resistance to cisplatin, USP1 has a high level of expression, and knock down of USP1 can significantly enhance cell sensitivity to cisplatin. In breast cancer cells, USP1 is highly expressed, promotes the proliferation of breast cancer cells and is closely related to the poor prognosis of breast cancer. As reported in the literature (J. Med. Chem. 2014, 57, 8099-8110, Synthesis and Structure-Activity Relationship Studies of N-Benzyl-2-phenylpyrimidin-4-amine Derivatives as Potent USP1/UAF1 Deubiquitinase Inhibitors with Anticancer Activity against Nonsmall Cell Lung Cancer), the compounds such as USP1 inhibitor ML323 can be used for non-small cell lung cancer. As reported in the literature (Cui S-Z, Lei Z-Y, Guan T-P, et al. Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy. Cancer Sci. 2020;00:1-15), USP1 inhibitors are used as potential therapeutic drugs for prostate cancer. In summary, USP1 is expected to become a hot target for treating various cancers and other diseases. CN202310473956.2 discloses a series of USP1 inhibitors, particularly compound 104 having the following structure: 4'-cyclopropyl-5,6'-dimethoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-[2,5'-bipyrimidin]-4-amine. However, no reports on the crystal form of this compound have been found in the prior art. SUMMARY OF THE INVENTION The technical problem to be solved by the present invention is to provide a crystal form of 4'-cyclopropyl-5,6'-dimethoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-[2,5'-bipyrimidin]-4-amine, a method for preparing the same and a use thereof. The inventors conducted extensive experimental research to discover a method capable of preparing a crystal form of 4'-cyclopropyl-5,6'-dimethoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-[2,5'-bipyrimidin]-4-amine, and X-ray powder diffraction analysis of the obtained crystal form revealed crystal form I with good stability. The present invention solves the above technical problem through the following technical solutions: The present invention provides crystal form I of 4'-cyclopropyl-5,6'-dimethoxy-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-[2,5'-bipyrimidin]-4-amine, characterized in that the X-ray powder diffraction pattern thereof comprises characteristic peaks at diffraction angles (2θ) of 6.378±0.2°, 9.521±0.2°, 15.721±0.2°, 16.379±0.2°, 16.981±0.2°, 17.560±0.2°, 19.080±0.2° and 22