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CN-121985944-A - Crystal of 7H-pyrrolo [2,3-d ] pyrimidin-4-amine derivative

CN121985944ACN 121985944 ACN121985944 ACN 121985944ACN-121985944-A

Abstract

The crystal form of N - (4- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) bicyclic [2.2.1] heptane-1-yl) -5-methylpyrazine-2-carboxamide (TAS3351) is a compound with EGFR inhibitory activity and an acid. This crystal form has advantageous physical properties, including stability, hygroscopicity, and oral absorption. This crystal form exhibits a peak at a specific diffraction angle (2 θ ± 0.2 °) in powder X-ray diffraction spectra.

Inventors

  • Murad Hamidi

Assignees

  • 大鹏药品工业株式会社

Dates

Publication Date
20260505
Application Date
20240927
Priority Date
20230929

Claims (20)

  1. 1. A crystal comprising N- (4- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) bicyclo [2.2.1] heptane-1-yl) -5-methylpyrazine-2-carboxamide and benzenesulfonic acid, wherein the crystal has peaks in the powder X-ray diffraction spectrum at the following diffraction angles (2Θ±0.2°): (i) At least one selected from 16.56 °, 19.2 °, 20.9 ° and 24.8 °, and (Ii) Two or more selected from 5.6 °, 6.0 °, 12.6 °, 14.0 °, 16.1 °, 20.2 °, 20.5 °, 23.9 °, 25.2 °, 26.1 °, 27.1 °, and 28.3 °.
  2. 2. The crystal according to claim 1, wherein the crystal has a peak at five or more diffraction angles (2Θ±0.2°) in total selected from (i) and (ii) in a powder X-ray diffraction spectrum.
  3. 3. The crystal according to claim 1, wherein the crystal has a peak at seven or more diffraction angles (2Θ±0.2°) in total selected from (i) and (ii) in a powder X-ray diffraction spectrum.
  4. 4. The crystal of claim 1, wherein the crystal has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in fig. 4.
  5. 5. The crystal of claim 1, wherein the exothermic peak measured in simultaneous thermogravimetric-differential thermal analysis is near 238 ℃.
  6. 6. The crystal according to claim 1, wherein the crystal has a crystal purity of 50% by weight or more.
  7. 7. The crystal of claim 1, wherein the crystal has a chemical purity of 90% or more.
  8. 8. A method of producing the crystal comprising N- (4- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) bicyclo [2.2.1] heptane-1-yl) -5-methylpyrazine-2-carboxamide and benzenesulfonic acid according to claim 1, which comprises stirring N- (4- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) bicyclo [2.2.1] heptane-1-yl) -5-methylpyrazine-2-carboxamide and benzenesulfonic acid in a single solvent of a lower alcohol having 2 or more carbon atoms, acetone or ethyl acetate, or in a mixed solvent comprising two or more of these solvents.
  9. 9. A crystal comprising N- (4- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) bicyclo [2.2.1] heptane-1-yl) -5-methylpyrazine-2-carboxamide and hydrochloric acid, wherein the crystal has peaks in the powder X-ray diffraction spectrum at the following diffraction angles (2Θ±0.2°): (i) 10.5 DEG and (Ii) At least two selected from 13.0 °, 17.7 °, 18.4 °, 20.8 °, 21.1 °, 23.6 ° and 24.1 °.
  10. 10. The crystal of claim 9, wherein the crystal has peaks in a powder X-ray diffraction spectrum at three or more diffraction angles (2Θ±0.2°) selected from (ii).
  11. 11. The crystal of claim 9, wherein the crystal has peaks in a powder X-ray diffraction spectrum at five or more diffraction angles (2Θ±0.2°) selected from (ii).
  12. 12. The crystal of claim 9, wherein the crystal has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in fig. 12.
  13. 13. The crystal of claim 9, wherein the exothermic peak measured in simultaneous thermogravimetric-differential thermal analysis is near 263 ℃.
  14. 14. The crystal according to claim 9, wherein the crystal has a crystal purity of 50% by weight or more.
  15. 15. The crystal of claim 9, wherein the crystal has a chemical purity of 90% or more.
  16. 16. A process for producing the crystal comprising N- (4- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) bicyclo [2.2.1] heptane-1-yl) -5-methylpyrazine-2-carboxamide and hydrochloric acid according to claim 9, which comprises stirring N- (4- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) bicyclo [2.2.1] heptane-1-yl) -5-methylpyrazine-2-carboxamide and hydrochloric acid in a single solvent of a lower alcohol having 2 or more carbon atoms, acetone or ethyl acetate, or in a mixed solvent comprising two or more of these solvents.
  17. 17. A crystal comprising N- (4- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) bicyclo [2.2.1] heptane-1-yl) -5-methylpyrazine-2-carboxamide and tartaric acid, wherein the crystal has peaks in the powder X-ray diffraction spectrum at the following diffraction angles (2θ±0.2°): (i) 12.2 DEG, and (Ii) At least two selected from 4.6 °, 6.3 °, 8.6 °, 9.1 °, 9.8 °, 12.1 °, 13.7 °, 18.3 ° and 20.6 °.
  18. 18. The crystal of claim 17, wherein the crystal has peaks in a powder X-ray diffraction spectrum at four or more diffraction angles (2Θ±0.2°) selected from (ii).
  19. 19. The crystal of claim 17, wherein the crystal has peaks in a powder X-ray diffraction spectrum at six or more diffraction angles (2Θ±0.2°) selected from (ii).
  20. 20. The crystal of claim 17, wherein the crystal has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in fig. 17.

Description

Crystal of 7H-pyrrolo [2,3-d ] pyrimidin-4-amine derivative Background EGFR is a receptor type tyrosine kinase that functions physiologically in normal tissues by binding to its ligand epidermal growth factor (EPIDERMAL GROWTH FACTOR, EGF) and contributes to proliferation of epithelial tissues and inhibits apoptosis. 1 EGF is the main component of the epithelial growth factor family (EGF). (Lacouture et al, nature REVIEWS CANCER, volume 6, pages 803-812). EGFR is also an oncogene, and amplification of EGFR gene and high expression or mutation of the protein are known to occur in various types of cancers such as head and neck cancer, breast cancer, colon cancer, esophagus cancer, pancreatic cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, skin cancer and brain tumor. (Kim et al Current Opinion in Oncology,2001, 13:506-513). Among them, the number of Lung Cancer death per year is up to about 140 ten thousand worldwide, and since non-small cell Lung Cancer accounts for more than 80% of all Lung cancers, there is a strong need to develop effective therapies [ Doebele, r.c. et al, lung Cancer,2010, 69, 1, 1-12]. Currently, various EGFR inhibitors have been reported as antitumor agents. JPWO2020166680A1 provides a compound N- (4- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) bicyclo [2.2.1] heptan-1-yl) -5-methylpyrazine-2-carboxamide (hereinafter referred to as "compound (1)" or "TAS 3351") having excellent EGFR inhibitory activity. JPWO2020166680A1 also provides a process for the preparation of compound (1). However, the document does not specifically mention what crystal form compound (1) or a salt thereof may be used. When the compounds are used as ingredients in pharmaceutical compositions, it is desirable to have a stable crystalline form of the compound to maintain stable quality and/or to facilitate storage management. In addition, crystalline forms of the compounds are expected to have low hygroscopicity, good oral absorbability, and the like. However, it is difficult to predict whether a particular compound or salt thereof will form crystals and what crystal form will have excellent stability and other physical properties. Under the above circumstances, there is a need to develop crystals of a compound or salt having EGFR inhibitory ability and having good stability, hygroscopicity and oral absorbability. Disclosure of Invention The present invention provides a salt form of N- (4- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) bicyclo [2.2.1] heptane-1-yl) -5-methylpyrazine-2-carboxamide (compound 1, tas 3351) having advantageous physical and pharmaceutical properties, whereby, for example, a highly effective, more convenient and controllable pharmaceutical formulation can be prepared for the treatment of diseases/disorders, such as various types of cancers, e.g., head and neck cancer, breast cancer, colon cancer, esophagus cancer, pancreas cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, skin cancer and brain tumor. The inventors of the present invention have discovered novel salt forms of compound (I) that possess desirable physical and pharmaceutical properties such as one or more of the following, ease of salification and crystallization (e.g., high yield), stable and well-defined physical properties (e.g., crystallinity, lack of polymorphism, high melting point and high melting enthalpy), moisture resistance stability, including at high humidity (hygroscopicity), desirable appearance (e.g., free flow, no adhesion/blocking, regular morphology), acceptable water solubility, and physiological acceptability, particularly suitable for pulmonary administration (e.g., no irritation), as well as other objects that will become apparent in the following detailed description. Provided herein are crystalline forms of a salt or co-crystal of compound (1) (TAS 3351) with benzenesulfonic acid, hydrochloric acid or tartaric acid that are useful as EGFR inhibitors. The salts or co-crystals of these compounds (1) are useful for the treatment of various types of cancers, such as head and neck cancer, breast cancer, colon cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, skin cancer and brain tumor. Accordingly, the present invention provides: (1) A crystal comprising N- (4- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) bicyclo [2.2.1] heptane-1-yl) -5-methylpyrazine-2-carboxamide and benzenesulfonic acid, wherein the crystal has peaks in the powder X-ray diffraction spectrum at diffraction angles (2Θ±0.2°) selected from one or more of 16.56 °, 19.2 °, 20.9 ° and 24.8 °, and (ii) selected from two or more of 5.6 °, 6.0 °, 12.6 °, 14.0 °, 16.1 °, 20.2 °, 20.5 °, 23.9 °, 25.2 °, 26.1 °, 27.1 ° and 28.3 °. (2) The crystal according to (1), wherein the crystal has a peak at five or more diffraction angles (2θ±0.2°) in total selected from the abo