CN-122029164-A - Crystal forms of triazolopyrimidinone derivatives

Abstract

The present invention relates to polymorphs of triazolopyrimidinone derivatives exhibiting tankyrase inhibitory activity and methods for preparing the same. The novel polymorphs of the present invention exhibit excellent non-hygroscopicity and stability, and exhibit excellent solubility and bioavailability, and thus are suitable as raw materials for pharmaceutical formulations.

Inventors

• Jin Xuyi
• Fang Yingtai

Assignees

• ST制药株式会社

Dates

Publication Date

20260512

Application Date

20231016

Claims (12)

1. 1. A crystalline form a of a compound represented by the following chemical formula I, the crystalline form a having a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ±0.2° of 6.31 °, 8.72 °, 10.92 °, 12.12 °, 13.16 ° and 15.98 °: [ formula I ] 。
2. 2. Form a of claim 1, wherein the powder X-ray diffraction pattern further comprises at least one peak at a diffraction angle 2Θ ± 0.2 ° of 5.43 °, 7.93 °, 17.56 °, or 18.22 °.
3. 3. Form a of claim 2, wherein the powder X-ray diffraction pattern further comprises at least one peak at diffraction angles 2Θ±0.2° of 20.63 °, 21.14 °, 22.23 °, 23.13 °, 23.98 °, 25.31 °, 26.08 °, 26.99 °, or 32.04 °.
4. 4. Form a of claim 1, wherein the form a has a melting point of 235 ℃ to 245 ℃ when the rate of temperature rise is 2 ℃ per minute.
5. 5. A process for preparing form a of the compound of formula I according to claims 1 to 4, the process comprising: (A-1) adding a mixed solvent of acetone and water to a compound represented by the following formula I, followed by stirring, and (A-2) filtering and drying the resulting solid: [ formula I ] 。
6. 6. The method according to claim 5, wherein the volume ratio of acetone and water in the mixed solvent is 4:6 to 6:4.
7. 7. A crystalline form B of a compound represented by the following chemical formula I, the crystalline form B having a powder X-ray diffraction pattern comprising peaks at diffraction angles 2Θ±0.2° of 7.83 °, 9.47 °, 10.24 °, 12.32 °, 15.16 °, and 16.29 °: [ formula I ] 。
8. 8. Form B of claim 7, wherein the powder X-ray diffraction pattern further comprises at least one peak at a diffraction angle 2Θ ± 0.2 ° of 6.12 °, 18.46 °, or 19.05 °.
9. 9. Form B of claim 8, wherein the powder X-ray diffraction pattern further comprises at least one peak at diffraction angles 2Θ±0.2° of 20.63 °, 21.33 °, 24.39 °, 25.19 °, 26.66 °, or 27.54 °.
10. 10. Form B of claim 7, wherein the form B has a melting point of 245 ℃ to 255 ℃ when the rate of temperature rise is 2 ℃ per minute.
11. 11. A process for preparing form B of the compound of formula I according to claims 7 to 10, the process comprising: (B-1) adding acetone, acetonitrile, 2-butanone, toluene or isopropanol to the compound represented by the following formula I, followed by stirring, and (B-2) filtering and drying the resulting solid: [ formula I ] 。
12. 12. A pharmaceutical composition for preventing or treating cancer, comprising form a according to claims 1 to 4 and form B according to claims 7 to 10.

Description

Crystal forms of triazolopyrimidinone derivatives Technical Field The present invention relates to crystalline forms of triazolopyrimidinone derivatives exhibiting tankyrase (tankyrase) inhibitory activity. The invention also relates to a process for preparing the crystalline form of the triazolopyrimidinone derivative. Background The tankyrase belongs to the family of poly (ADP-ribose) polymerase (PARP) proteins consisting of 17 members sharing a catalytic PARP domain (CATALYTIC PARP domain). Recently, intracellular levels of proteins have been reported to be affected by the PARP enzyme family members, tankyrase-1 and tankyrase-2 (also known as PARP5a and PARP5b, respectively) (Huang et al 2009, nature, 461 (7264): 614-620). Inhibitors of tankyrase-1 and tankyrase-2 are known to be useful in the treatment of various solid tumors, such as colorectal cancer, colon cancer, gastric cancer, hepatocellular carcinoma, breast cancer, medulloblastoma, melanoma, non-small cell lung cancer, pancreatic adenocarcinoma, and prostate cancer. Furthermore, in addition to cancer diseases, inhibitors of tankyrase-1 and tankyrase-2 have therapeutic potential for other diseases, including osteoporosis, osteoarthritis, polycystic kidney disease, pulmonary fibrosis, diabetes, schizophrenia, vascular diseases, heart diseases, non-oncogenic proliferative diseases, and neurodegenerative diseases such as Alzheimer's disease. As described above, there is a continuing need for new therapeutic agents that can be used in cancer and hyperproliferative disorders, and efforts are being made to develop new pharmaceutical compounds that can selectively inhibit tankyrase. In particular, triazolopyrimidinone derivatives of the following formula I are known as selective tankyrase inhibitors (international patent publication No. WO 2016/006974) and are being developed as therapeutic agents for colorectal cancer in patients having a genotype of mutation of the gene inducing colorectal cancer (KRAS: kirsten rat sarcoma virus) or patients that are nonresponsive to Erbitux (Erbitux) (European Journal of Cancer, 173, (2022), 41-51). [ Formula I ] In the manufacture of medicaments, the physical state of the drug substance, i.e. whether crystalline or amorphous, is critical in designing an appropriate dosage form. However, the crystalline starting material has low solubility, which may lead to reduced bioavailability per unit weight. In contrast, amorphous forms are unstable and can present challenges in controlling drug release and blood concentration levels. Accordingly, there is a need to develop novel crystalline forms of triazolopyrimidinone derivatives of formula I that overcome these limitations while exhibiting improved physicochemical properties. Disclosure of Invention Technical problem The present invention aims to provide a crystalline form of a triazolopyrimidinone derivative having excellent non-hygroscopicity and stability, and a process for producing the same. It is another object of the present invention to provide a crystalline form of a triazolopyrimidinone derivative capable of improving solubility and bioavailability, and a method for preparing the same. Technical proposal In order to achieve the above object, the present inventors have studied and made efforts to prepare crystalline forms a and B described below, and confirmed that all of these crystalline forms exhibit excellent effects, thereby completing the present disclosure. Detailed Description Crystal form A and preparation method thereof The present invention provides a crystalline form a of a compound represented by the following chemical formula I, the crystalline form a having a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ±0.2° of 6.31 °, 8.72 °, 10.92 °, 12.12 °, 13.16 ° and 15.98 °: [ formula I ] According to an embodiment of the present invention, the powder X-ray diffraction pattern of form a may further comprise at least one peak at diffraction angles 2θ±0.2° of 5.43 °, 7.93 °, 17.56 ° or 18.22 °. According to an embodiment of the present invention, the powder X-ray diffraction pattern of form a may further comprise at least one peak at diffraction angles 2θ±0.2° of 20.63 °, 21.14 °, 22.23 °, 23.13 °, 23.98 °, 25.31 °, 26.08 °, 26.99 ° or 32.04 °. According to embodiments of the present invention, when the rate of temperature increase is 2 ℃ per minute, the form a may have a melting point of 235 ℃ to 245 ℃, and in particular may have a melting point of about 238 ℃ to about 242 ℃. More specifically, when the rate of temperature rise is 2 ℃ per minute, the form a may have a melting point of about 239.7 ℃. Furthermore, the present invention provides a process for preparing said form a. Specifically, the preparation method can comprise the following steps: (A-1) adding a mixed solvent of acetone and water to a compound represented by the following formula I, followed by stirring, and (A-2) filtration and drying of the resulting solid. Acc