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CA-3186562-C - SALT AND CRYSTAL FORM OF DIHYDROPYRIDO[2,3-D]PYRIMIDINE DERIVATE

CA3186562CCA 3186562 CCA3186562 CCA 3186562CCA-3186562-C

Abstract

Disclosed in the present application are a salt and crystal form of a dihydropyrido[2,3-d]pyrimidine derivate, and specifically, a crystal form of a fumarate hydrate of compound 1, and a preparation method therefor. The crystal from has good stability and can better be applied to clinical practice.

Inventors

  • Jian Wu
  • CHANGYOU MA
  • He Tian
  • Jianliang Zhao
  • Donghui Chen
  • Dan Xu
  • Chunxia Zhu
  • Zhoushan Tian

Assignees

  • NANJING CHIA TAI TIANQING PHARMACEUTICAL CO., LTD.

Dates

Publication Date
20260505
Application Date
20210722
Priority Date
20200722

Claims (20)

  1. Claims 1. A crystal form of a fumarate hydrate having the following structure, the crystal form is crystal form A, wherein, X is 2.0-3.0, and an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Ka radiation 5 has characteristic peaks at 2θ values of 9.28°±0.2° and 23.63°±0.2°.
  2. 2. The crystal form according to claim 1, wherein the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 2θ values of 9.28°±0.2°, 19.45°±0.2°, 21.60°±0.2°, and 23.63°±0.2°.
  3. 3. The crystal form according to claim 1, wherein the X-ray powder diffraction pattern expressed in 2θ angles has 10 characteristic peaks at 2θ values of 9.28°±0.2°, 14.22°±0.2°, 19.45°±0.2°, 21.60°±0.2°, and 23.63°±0.2°.
  4. 4. The crystal form according to claim 1, wherein the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 2θ values of 9.28°±0.2°, 10.72°±0.2°, 14.22°±0.2°, 19.45°±0.2°, 21.60°±0.2°, 23.63°±0.2°, 24.50°±0.2°, 24.83°±0.2°, 25.08°±0.2°, and 30.33°±0.2°.
  5. 5. The crystal form according to claim 1, wherein the X-ray powder diffraction pattern expressed in 2θ angles has 15 characteristic peaks at 2θ values of 5.29°±0.2°, 9.28°±0.2°, 10.72°±0.2°, 11.24°±0.2°, 12.13°±0.2°, 12.51°±0.2°, 13.60°±0.2°, 14.22°±0.2°, 15.64±0.2°, 16.14°±0.2°, 16.52°±0.2°, 17.38°±0.2°, 17.99°±0.2°, 18.68°±0.2°, 19.00°±0.2°, 19.45°±0.2°, 19.80°±0.2°, 20.53°±0.2°, 21.60°±0.2°, 21.89°±0.2°, 22.58°±0.2°, 23.63°±0.2°, 24.50°±0.2°, 24.83°±0.2°, 25.08°±0.2°, 25.66°±0.2°, 26.09°±0.2°, 26.84°±0.2°, 27.43°±0.2°, 27.94°±0.2°, 28.81°±0.2°, 29.52°±0.2°, 29.98°±0.2°, 30.33°±0.2°, 30.92°±0.2°, 32.03°±0.2°, 32.80°±0.2°, 33.34°±0.2°, 20 34.14°±0.2°, 34.72°±0.2°, 35.83°±0.2°, 36.55°±0.2°, 37.35°±0.2°, 38.11°±0.2°, and 38.93°±0.2°.
  6. 6. The crystal form according to claim 1, wherein the X-ray powder diffraction pattern expressed in 2θ angles is shown as Fig. 4, or shown as Fig. 8, or shown as Fig. 10.
  7. 7. The crystal form according to claim 1, wherein a thermogram of crystal form A that is obtained by differential scanning calorimetry has an endothermic peak at the onset temperature of 118-128°C. 25
  8. 8. The crystal form according to claim 1, wherein a thermogram of crystal form A that is obtained by differential scanning calorimetry has an endothermic peak at the onset temperature of 120-125°C.
  9. 9. The crystal form according to claim 1, wherein a thermogram of crystal form A that is obtained by differential scanning calorimetry has an endothermic peak at the onset temperature of 123°C. CA3,186,562 MTPICA220604 21
  10. 10. The crystal form according to claim 1, wherein the DSC pattern is shown as Fig. 5.
  11. 11. The crystal form according to claim 1, wherein a spectrum of crystal form A that is obtained by attenuated total reflectance Fourier transform infrared spectroscopy has the following absorption bands expressed in reciprocals of wavelengths (cm-1): 3451±2, 2981±2, 2953±2, 2882±2, 2824±2, 2477±2, 1698±2, 1631±2, 1596±2, 1544±2, 5 1490±2, 1465±2, 1441±2, 1390±2, 1362±2, 1320±2, 1302±2, 1283±2, 1254±2, 1197±2, 1135±2, 1091±2, 1058±2, 1014±2, 983±2, 929±2, 894±2, 867±2, 834±2, 802±2, 784±2, 761±2, 739±2, 718±2, 663±2, 647±2, 640±2, 584±2, 560±2, and 497±2.
  12. 12. The crystal form according to claim 1, wherein a spectrum of crystal form A that is obtained by Fourier transform Raman spectroscopy has the following absorption bands expressed in reciprocals of wavelengths (cm-1): 10 1699±2, 1664±2, 1602±2, 1340±2, 867±2, 829±2, 809±2, 747±2, 669±2.
  13. 13. The crystal form according to claim 1, wherein the TGA pattern is shown as Fig. 6, or shown as Fig. 7, or shown as Fig. 9.
  14. 14. A preparation method of the crystal form according to any one of claims 1 to 13, comprising a step of adding a seed crystal of crystal form A during salification reaction of compound 1 with fumaric acid; or dissolving an 15 amorphous fumarate of compound 1 in water, and performing suction filtration and vacuum drying, wherein the compound 1 has the following structure: .
  15. 15. A pharmaceutical composition, the composition comprising the crystal form according to any one of claims 1 to 13, and one or more pharmaceutically acceptable carriers. 20
  16. 16. The crystal form according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 15 for use as a medicament.
  17. 17. Use of the crystal form according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 15 in the prevention and/or treatment of an AKT protein kinase-mediated disease or disease state, or in the preparation of a medicament for preventing and/or treating an AKT protein kinase-mediated disease or disease 25 state.
  18. 18. Use of the crystal form according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 15 for prevention and/or treatment of an AKT protein kinase-mediated disease or disease state.
  19. 19. The use according to claim 17 or 18, wherein the AKT protein kinase-mediated disease or disease state is cancer. CA3,186,562 MTPICA220604 22
  20. 20. The use according to claim 19, wherein the cancer isbreast cancer, prostate cancer or ovarian cancer.

Description

1 Description SALT AND CRYSTAL FORM OF DIHYDROPYRIDO[2,3 d ]PYRIMIDINE DERIVATE The present application claims priority to Chinese Patent Application No. 202010709837.9 entitled " Salt and Crystal Form of D ihydropyrido[2,3 d]pyrimidine D erivate " and filed wit h the China Patent Office on July 22, 2020. TECHNICAL FIELD The present application belongs to the field of medici nal chemistry, and specifically relates to a salt of dihydropyrido[2,3 d]pyrimidinone derivative, a crystal form thereof, and a preparation m ethod and medical use thereof. BACKGROUND The PI3K/AKT/mTOR pathway consisting of phosphoinositide 3 kinase (PI3K) and its downstream protein AKT (also known as protein kinase B PKB), and mammalian target of Rapamycin (mTOR) as a very important intracell ular signal transduction pathway, the pathway exerts an extremely important biological function in the process of cell growth, survival, proliferation, apoptosis, angiogenesis, autophagy, etc. Abnormal activation of the 15 pathway will cause a series of disea ses such as cancer, neuropathy, autoimmune disease, and hemolymphatic system disease. AKT is a type of serine/threonine kinase and affects the survival, growth, metabolism, proliferation, migration, and differentiation of cell through numerous downstream e ffectors. Overactivation of AKT has been observed in more than 50% of human tumors, especially in prostate cancer, pancreatic cancer, bladder cancer, ovarian cancer, and 20 breast cancer. Overactivation of AKT may lead to the formation, metastasis, and drug r esistance of tumor. AKT has three isoforms: AKT1, AKT2, and AKT3. As a typical protein kinase, each isoform consists of an amino terminal pleckstrin homology (PH) domain, a middle ATP binding kinase domain, and a carboxy l terminal regulatory domain. About 80% amino acid sequence s of the three isoforms are homologous, and only the amino acid sequences in a binding domain between the PH domain and the kinase domain changes greatly 25 The current drugs targeting the PI3K/AKT/mTOR signaling pathway mainly include PI3K inhibitors and mTOR inhibitors, while AKT is at the core of the signal transduction pathway. Inhibition of the AKT activity can not only avoid the severe side effects caused by inhibition of upstream PI3K, but also avoid the negative feedback mechani sm caused by inhibition of downstream mTOR from affecting the efficacy of a drug. For example, CN101631778A discloses a class of c yclopentadiene [D]pyrimidine derivatives, CN101578273A discloses a class of 30 hydroxylated and methoxylated c yclopentadiene [D]pyr imidine derivatives, CN101511842A discloses a class of dihydrofuropyrimidine derivatives, CN101970415A discloses a class of 5H c yclopentadiene [d]pyrimidine derivatives, and these compounds inhibit AKT1 with IC 50 less than 10 µM. However, development of eff ective and selective AKT inhibitors is still an important direction for current development of tumor targeting drugs. 35 CA 3186562 CA3,186,562 MTPICA220604 2 SUMMARY OF THE INVENTION In one aspect, the present application provides a crystal form (hereinafter referred to as crystal form A) of a fumarate hydrate having the following structure: 5 where, X is 2.0-3.0, and an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Ka radiation has characteristic peaks at 2θ values of 9.28°±0.2° and 3.63°±0.2°. The above said fumarate hydrate is a fumarate hydrate of compound 1, wherein the compound 1 has the following structure: 10 . In some embodiments, the X-ray powder diffraction pattern expressed in 2θ angles of crystal form A has characteristic peaks at 2θ values of 9.28°±0.2°, 19.45°±0.2°, 21.60°±0.2°, and 23.63°±0.2°. In some embodiments, the X-ray powder diffraction pattern expressed in 2θ angles of crystal form A has characteristic peaks at 2θ values of 9.28°±0.2°, 14.22°±0.2°, 19.45°±0.2°, 21.60°±0.2°, and 23.63°±0.2°. 15 In some embodiments, the X-ray powder diffraction pattern expressed in 2θ angles of crystal form A has characteristic peaks at 2θ values of 9.28°±0.2°, 10.72°±0.2°, 14.22°±0.2°, 19.45°±0.2°, 21.60°±0.2°, 23.63°±0.2°, 24.50°±0.2°, 24.83°±0.2°, 25.08°±0.2°, and 30.33°±0.2°. In some embodiments, the X-ray powder diffraction pattern expressed in 2θ angles of crystal form A has characteristic peaks at 2θ values of 5.29°±0.2°, 9.28°±0.2°, 10.72°±0.2°, 11.24°±0.2°, 12.13°±0.2°, 12.51°±0.2°, 20 13.60°±0.2°, 14.22°±0.2°, 15.64±0.2°, 16.14°±0.2°, 16.52°±0.2°, 17.38°±0.2°, 17.99°±0.2°, 18.68°±0.2°, 19.00°±0.2°, 19.45°±0.2°, 19.80°±0.2°, 20.53°±0.2°, 21.60°±0.2°, 21.89°±0.2°, 22.58°±0.2°, 23.63°±0.2°, CA3,186,562 MTPICA220604 3 24.50°±0.2°, 24.83°±0.2° 24.50°±0.2°, 24.83°±0.2°, 25.08°±0.2°, 25.66°±0.2°, 26.09°±0.2°, 26.84°±0.2°, 27.43°±0.2°, 27.94°±0.2°, , 25.08°±0.2°, 25.66°±0.2°, 26.09°±0.2°, 26.84°±0.2°, 27.43°±0.2°, 27.94°±0.2°, 28.81°±0.2°, 29.52°±0.2°, 29.98°±0.2°, 30.33°±0.2°, 30.92°±0.2°, 32.03°±0.2°, 32.80°±0.2°, 33.34°±0.2°, 28.81°±0.2°, 29.52°±0.2°, 29.98°±0.2°, 30.33°±0.2°, 30.92°±