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CN-117642405-B - Salt form of tricyclic tetrahydroisoquinoline derivative

CN117642405BCN 117642405 BCN117642405 BCN 117642405BCN-117642405-B

Abstract

The present disclosure relates to a salt form of tricyclic tetrahydroisoquinoline derivatives. In particular, the present disclosure relates to different salt forms of a compound of formula (I) and methods for preparing the same, and the salt forms of the compound of formula (I) provided by the present disclosure have good stability and can be better used for clinical treatment.

Inventors

  • JIA LINA
  • WANG LIN
  • SHAO QIYUN
  • FENG JUN
  • YANG JUNRAN
  • DU ZHENXING

Assignees

  • 江苏恒瑞医药股份有限公司
  • 上海恒瑞医药有限公司

Dates

Publication Date
20260512
Application Date
20220708
Priority Date
20210709

Claims (20)

  1. 1. A pharmaceutically acceptable salt of a compound of formula (I) selected from the group consisting of phosphate, sulfate, tartrate, citrate, hydrochloride, hydrobromide, mesylate, formate, acetate, succinate, maleate, malate and p-toluenesulfonate, 。
  2. 2. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 1, wherein the ratio of the amount of the compound of formula (I) to the amount of the substance of the acid molecule is selected from the group consisting of 5:1-1:5.
  3. 3. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, wherein the ratio of the amount of the compound of formula (I) to the amount of the substance of the acid molecule is selected from 1:1 or 1:3.
  4. 4. A pharmaceutically acceptable salt of a compound of formula (I) according to claim 3, which is a phosphate salt, wherein the mass ratio of the compound of formula (I) to the phosphate molecule is 1:3.
  5. 5. A crystalline form I of a phosphate salt of a compound represented by formula (I) according to claim 1, wherein the mass ratio of the compound represented by formula (I) to the phosphoric acid molecule is 1:3, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2 theta has characteristic peaks at 6.1, 13.5, 19.2, 22.3, 。
  6. 6. The form I of the phosphate salt of the compound represented by formula (I) according to claim 5, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ has characteristic peaks at 6.1, 13.5, 13.9, 19.2, 21.8, 22.3, 23.4.
  7. 7. The form I of the phosphate salt of the compound represented by formula (I) according to claim 5, having characteristic peaks at 6.1, 12.4, 13.5, 13.9, 15.0, 16.3, 16.9, 19.2, 20.8, 21.8, 22.3, 23.4, 24.1, 24.6, 26.2, 27.5, 30.0 in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ.
  8. 8. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, which is a sulfate salt, wherein the mass ratio of the compound of formula (I) to the sulfuric acid molecule is 1:1.
  9. 9. A crystalline form A of a sulfate salt of a compound represented by the formula (I) according to claim 1, wherein the mass ratio of the compound represented by the formula (I) to the sulfuric acid molecule is 1:1, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 theta has characteristic peaks at 6.6, 7.9, 15.1, 20.7, 22.1, 。
  10. 10. Form a of the sulfate salt of the compound of formula (I) according to claim 9, having characteristic peaks at 6.6, 7.9, 13.4, 14.5, 15.1, 19.3, 19.8, 20.7, 22.1, 24.8, 25.4, 25.7, 27.6 in terms of the X-ray powder diffraction pattern expressed in terms of the angle of diffraction 2Θ.
  11. 11. Form a of the sulfate salt of the compound of formula (I) according to claim 9, having characteristic peaks at 6.6, 7.9, 11.6, 13.4, 14.5, 15.1, 15.9, 18.1, 19.3, 19.8, 20.7, 22.1, 24.0, 24.8, 25.4, 25.7, 27.2, 27.6, 28.3, 29.2 in terms of the X-ray powder diffraction pattern expressed in terms of the angle of diffraction 2Θ.
  12. 12. A crystalline form of a pharmaceutically acceptable salt of a compound of formula (I) according to any one of claims 5-7 or 9-11, wherein the error in the 2Θ angle is within ± 0.2.
  13. 13. A process for the preparation of a phosphate salt of a compound of formula (I) according to any one of claims 1 to 4, or a crystalline form I of a phosphate salt of a compound of formula (I) according to any one of claims 5 to 7, comprising the step of reacting a compound of formula (I) with phosphoric acid.
  14. 14. A process for the preparation of the form I of the phosphate salt of a compound of formula (I) according to any one of claims 5 to 7, comprising the steps of: 1) Preparing a solvent A solution of a compound shown in a formula (I), wherein the solvent A is selected from ketone solvents, ester solvents or ether solvents; 2) Preparing a solvent B solution of phosphoric acid, wherein the solvent B is selected from water or alcohol solvents; 3) Mixing the solvent A solution of the compound shown in the formula (I) with the solvent B solution of phosphoric acid, and crystallizing out.
  15. 15. The process for preparing the form I of the phosphate of the compound of formula (I) according to claim 14, wherein the solvent A is selected from acetone, ethyl acetate or methyl tert-butyl ether, and the solvent B is selected from methanol, ethanol or water.
  16. 16. A process for the preparation of the form a of the sulphate salt of a compound of formula (I) according to any one of claims 1 to 3 or 8 or according to any one of claims 9 to 11, comprising the step of reacting a compound of formula (I) with sulphuric acid.
  17. 17. A process for the preparation of form a of the sulphate salt of a compound of formula (I) according to any one of claims 9 to 11 comprising the steps of: 1) Preparing a solvent A solution of a compound shown in a formula (I), wherein the solvent A is selected from ketone solvents, ester solvents or alcohol solvents; 2) Preparing a solvent B solution of sulfuric acid, wherein the solvent B is selected from water or alcohol solvents; 3) Mixing solvent A solution of the compound shown in formula (I) with solvent B solution of sulfuric acid, and crystallizing.
  18. 18. The process for preparing the form A of the sulfate salt of the compound of formula (I) according to claim 17, wherein the solvent A is selected from acetone, ethyl acetate, methanol or ethanol, and the solvent B is selected from methanol, ethanol or water.
  19. 19. A process for the preparation of a pharmaceutically acceptable salt of a compound of formula (I) as claimed in claim 1, comprising the step of reacting a compound of formula (I) with tartaric acid, citric acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, formic acid, acetic acid, succinic acid, maleic acid, malic acid or p-toluenesulfonic acid to form a salt.
  20. 20. A pharmaceutical composition comprising the following ingredients: 1) A pharmaceutically acceptable salt of a compound of formula (I) according to any one of claims 1 to 4, 8 or a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I) according to any one of claims 5 to 7, 9 to 12, or a mixture thereof, and 2) Optionally from a pharmaceutically acceptable carrier or excipient.

Description

Salt form of tricyclic tetrahydroisoquinoline derivative The present application claims priority from chinese patent application 2021107799053, whose filing date is 2021, 7, 9. The present application incorporates the entirety of the above-mentioned chinese patent application. Technical Field The present disclosure relates to a salt form of tricyclic tetrahydroisoquinoline derivative, a preparation method and medical application thereof, and belongs to the field of pharmacy. Background In CSCO breast cancer diagnosis and treatment guidelines (2020 edition), fulvestrant is regulated to be a class I recommendation for patients with advanced breast cancer positive to hormone receptors of non-endocrine therapists, a class II recommendation is newly added fulvestrant and CDK4/6 inhibitor, and in addition, the fulvestrant combined with CDK4/6 inhibitor is already a class I recommendation for patients with non-steroidal AI (NSAI) treatment failure and Steroidal AI (SAI) treatment failure, wherein fulvestrant is used as the only SERD in the current batch, and the batch is in the form of injection, so that inconvenience is brought to patients for medication. Therefore, searching for new and more effective SERD not only has huge market value, but also brings medicine selectivity and convenience for breast cancer patients. SAI439859 of Sainofil is currently in clinical stage III as a new generation of orally available SERD inhibitor, and in addition, GDC-9545 of Roche, AZD-9833 of Aspirinotecan, and RAD1901 of Radius all enter stage III. Published patent applications for selective estrogen receptor mediated modulators include WO2014165723, WO2014151899, WO2014141292, WO2014191726, WO2015092634, WO2014135834, WO2014106848 and EP1113007. PCT application WO2021139756A discloses that tricyclic tetrahydroisoquinoline derivatives shown in formula (I) are used for estrogen receptor downregulation (SERD), and in order to meet the requirement of medication, the research on salts and crystal forms thereof is necessary, Disclosure of Invention The present disclosure provides a pharmaceutically acceptable salt of a compound of formula (I) selected from the group consisting of phosphate, sulfate, tartrate, citrate, hydrochloride, hydrobromide, mesylate, formate, acetate, succinate, maleate, malate, or p-toluenesulfonate, In some embodiments, the present disclosure provides pharmaceutically acceptable salts of compounds of formula (I), wherein the ratio of the amount of the compound of formula (I) to the amount of the substance of the acid molecule is selected from 1:5 to 5:1. In some embodiments, the present disclosure provides pharmaceutically acceptable salts of compounds of formula (I), wherein the amount ratio of the compound of formula (I) to the substance of the acid molecule is 1:1. In some embodiments, the present disclosure provides pharmaceutically acceptable salts of compounds of formula (I), wherein the amount ratio of the compound of formula (I) to the substance of the acid molecule is 1:3. In some embodiments, the present disclosure provides a phosphate salt of a compound of formula (I), wherein the amount ratio of the compound of formula (I) to the substance of the phosphate molecule is 1:3. The present disclosure provides a form I of a phosphate salt of a compound of formula (I), wherein the compound of formula (I) has a mass ratio of the compound to the phosphate molecule of 1:3, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, and characteristic peaks at 6.1, 13.5, 19.2, 22.3. In some embodiments, the phosphate salt of the compound of formula (I) has a mass ratio of the compound of formula (I) to the phosphate molecule of 1:3, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, and characteristic peaks at 6.1, 13.5, 13.9, 19.2, 21.8, 22.3, 23.4. In some embodiments, the phosphate salt of the compound of formula (I) has a mass ratio of the compound of formula (I) to the phosphate molecule of 1:3, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, and characteristic peaks at 6.1, 12.4, 13.5, 13.9, 15.0, 16.3, 16.9, 19.2, 20.8, 21.8, 22.3, 23.4, 24.1, 24.6, 26.2, 27.5, 30.0. In some embodiments, the compound of formula (I) is present in the form I of the phosphate salt, wherein the ratio of the compound of formula (I) to the phosphate molecule is 1:3, and the X-ray powder diffraction pattern expressed in terms of diffraction angle 2. Theta. Is as shown in figure 2. In some embodiments, the phosphate salt of the compound of formula (I) is in form I, wherein the ratio of the compound of formula (I) to the phosphate molecule is 1:3, triclinic, axial lengthAxis angle α= 89.575 (2) °, β= 89.859 (2) °, γ= 60.745 (2) °, unit cell volume The present disclosure provides a method for preparing a phosphate of a compound represented by formula (I) or a form I of a phosphate of a compound represented by formula (I), comprising a step of react