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JP-7857417-B2 - Crystalline polymorphs of JAK tyrosine kinase inhibitors and methods for producing the same

JP7857417B2JP 7857417 B2JP7857417 B2JP 7857417B2JP-7857417-B2

Inventors

  • マ，スーフェン
  • ルオ，ファソン
  • ハン，ジュンル
  • フウ，ウェイ
  • シュウ，リー

Assignees

  • プライム ジーン セラピューティクス カンパニー リミテッド

Dates

Publication Date
20260512
Application Date
20230224
Priority Date
20220224

Claims (11)

  1. A crystal of crystalline form I of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile, A crystal characterized by having 2θ values of characteristic peaks in its powder X-ray diffraction pattern of 6.48, 13.01, 15.38, 19.61, 20.68, 23.47, and 26.29, with a measurement error of ±0.2 degrees.
  2. The crystal according to claim 1, A crystal characterized in that the 2θ values of the characteristic peaks in the powder X-ray diffraction pattern are 6.48, 7.68, 9.90, 13.01, 14.81, 15.38, 16.43, 16.87, 19.61, 20.68, 23.47, 26.29, and 32.23, and the measurement error is ±0.2 degrees.
  3. A crystal of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile of crystalline form IIb, A crystal characterized by having 2θ values of characteristic peaks in its powder X-ray diffraction pattern of 7.93, 9.36, 11.29, 14.95, 20.96, 21.36, 21.77, 22.12, and 22.79, with a measurement error of ±0.2 degrees.
  4. The crystal according to claim 3, A crystal characterized in that the 2θ values of characteristic peaks in the powder X-ray diffraction pattern are 7.93, 9.36, 11.29, 14.69, 14.95, 15.13, 15.95, 19.93, 20.15, 20.96, 21.36, 21.77, 22.12, 22.79, 23.54, 24.14, 26.38, 28.74, and 29.15, and the measurement error is ±0.2 degrees.
  5. The crystal according to claim 3, A crystal characterized by being a hemihydrate.
  6. The crystal according to claim 4, A crystal characterized by being a hemihydrate.
  7. An oral pharmaceutical composition comprising the crystal described in claim 1 or 2.
  8. A topical pharmaceutical composition comprising the crystal described in any one of claims 3 to 6.
  9. Use of the crystal according to any one of claims 1 to 6 in the manufacture of a drug for treating Janus kinase-mediated diseases.
  10. Use of the oral pharmaceutical composition according to claim 7 in the manufacture of a drug for treating Janus kinase-mediated diseases.
  11. Use of the topical pharmaceutical composition according to claim 8 in the manufacture of a drug for treating Janus kinase-mediated diseases.

Description

This application relates to the field of chemical pharmaceuticals and concerns the crystalline polymorphism of chemical drugs. Specifically, it relates to the crystalline polymorphism of the compound 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile and a method for producing the same. 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile (compound A) belongs to the non-receptor tyrosine kinase inhibitors of the JAK class of small molecules. Its JAK-STAT signaling pathway is closely related to inflammatory cytokines and tumors and is widely involved in important biological processes in human health and disease, such as cell proliferation, differentiation, metastasis and apoptosis, and the regulation of immune responses and cellular homeostasis. The structural formula of compound A is as follows: The synthesis method for this compound is disclosed in the invention's patent CN201711248509.8, but the crystalline form of the compound is not mentioned, and the crystalline form of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile has not been reported in other literature. However, the crystalline polymorphism of a drug is of significant importance to its physical properties, bioavailability, formulation quality, and process. Drugs with crystalline polymorphism have differences in physicochemical properties depending on the crystalline form, which affects the stability of the drug. When the drug is the same but has different crystalline forms, their bioavailability may differ significantly. Different crystalline forms affect the drug's dissolution rate. Also, differences in the surface free energy of different crystalline forms result in different bonding forces between crystal particles, which affects the drug's fluidity, particle uniformity, content uniformity, and physical stability. Therefore, it is necessary to consider the crystal type. The object of this application is to provide a crystalline polymorph of compound A, whose chemical name is 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile, and a method for producing the same. The method for synthesizing compound A is disclosed in the invention patent CN201711248509.8, and compound A produced by reference to said invention patent is used in the production of the crystalline polymorph in this application. According to one embodiment, the present application provides a crystalline polymorph of compound A. This application provides crystalline polymorphs of drug compound A, which include many crystalline forms of compound A, such as crystalline form I, crystalline form IIa, crystalline form IIb, and crystalline form III. This application further provides crystalline forms of salts of compound A. Figure 1 shows the powder X-ray diffraction pattern of crystalline form I of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile of the present application, where the measurement error of 2θ is ±0.2 degrees, and as shown in the table below, it contains multiple characteristic peaks between 0 and 40 degrees. Crystal type I according to this application showed no exothermic or endothermic peaks between 50 and 200°C on differential scanning calorimeter (DSC), but exhibited endothermic peaks around 213.5°C, 219.6°C, and 229.0°C, with a clear exothermic peak between 213.5°C and 229.0°C. The differential scanning calorimetry curve of crystal type I indicated that a crystal transition occurred during the heating and melting process. It was shown that after the sample melted endothermally at approximately 213.5°C, it exothermically transitioned to a more stable crystal type, and as the temperature further increased, the newly formed crystal type melted endothermically. While the crystal transition demonstrated the relative magnitude of stability (melting point, lattice energy) between different crystal types, such changes occurred at relatively high temperatures (>200.0°C) and do not correspond to the stability of crystal types under normal operating conditions. Crystalline form I of this application does not contain crystal water and does not contain a crystal solvent. This application relates to crystalline form IIa of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile. The powder X-ray diffraction pattern of crystalline form IIa is shown in Figure 3, where the measurement error of 2θ is ±0.2 degrees, and several characteristic peaks included between 0 and 40 degrees are shown in the table below. Crystal type IIa according to this application was shown to have no endothermic peak between 50 and 200°C, but to have an endothermic peak around 220.2°C, as measured by differential scann