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RU-2026112595-A - Pharmaceutically acceptable salt and crystal form of quinazoline derivative and their use

RU2026112595ARU 2026112595 ARU2026112595 ARU 2026112595ARU-2026112595-A

Inventors

  • ВАН, Цзе
  • ЯН, Цзюньжань
  • ДУ, Чжэньсин
  • ВАН, Цзе

Assignees

  • ЦЗЯНСУ ХЭНЖУЙ ФАРМАСЬЮТИКАЛЗ КО., ЛТД.
  • ШАНХАЙ ХЭНЖУЙ ФАРМАСЬЮТИКАЛ КО., ЛТД.

Dates

Publication Date
20260505
Application Date
20240927
Priority Date
20230927

Claims (16)

  1. 1. A pharmaceutically acceptable salt of 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one represented by formula 1, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, methanesulfonate, tartrate, p-toluenesulfonate and fumarate,
  2. 2. A pharmaceutically acceptable salt according to claim 1, wherein the chemical ratio of 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one and the acid is from 3:1 to 1:3, preferably from 2:1 to 1:2, more preferably 1:1 or 1:2.
  3. 3. A method for producing a pharmaceutically acceptable salt of 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one, comprising the step of subjecting 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one to a reaction with an acid, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, fumaric acid, p-toluenesulfonic acid and tartaric acid.
  4. 4. 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one methanesulfonate, where the chemical ratio of 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one and methanesulfonic acid is 1:1.
  5. 5. Crystalline Form I of the methanesulfonate of the compound of formula 1, wherein its powder X-ray diffraction pattern expressed in terms of the diffraction angle 2θ has characteristic peaks at 12.785, 14.363, 18.248, 19.608, 20.315 and 25.404, preferably has characteristic peaks at 8.311, 12.785, 14.363, 15.220, 17.817, 18.248, 19.318, 19.608, 20.315, 21.697, 22.256, 25.404 and 28.858 and more preferably has characteristic peaks at 8.311, 9.846, 12.785, 14,363, 15,220, 16,576, 17,817, 18,248, 19,318, 19,608, 20,315, 21,697, 22,256, 24,601, 25,404, 27,594, 28,858 and 31,581,
  6. 6. The crystalline form according to claim 5, wherein the powder X-ray diffraction pattern expressed using the diffraction angle 2θ is as shown in Fig. 8.
  7. 7. A method for producing a crystalline form according to claim 5 or 6, comprising dissolving a compound of formula 1 in acetone, adding an aqueous solution of methanesulfonic acid and stirring the mixture.
  8. 8. 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one p-Toluenesulfonate, wherein the chemical ratio of 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one and p-toluenesulfonic acid is 1:1.
  9. 9. Crystalline Form I of p-toluenesulfonate of the compound of formula 1, wherein its powder X-ray diffraction pattern, expressed in terms of the diffraction angle 2θ, has characteristic peaks at 6.708, 9.145, 15.275, 17.217, 20.971 and 22.499, preferably has characteristic peaks at 6.708, 8.935, 9.145, 13.450, 15.275, 16.934, 17.217, 18.123, 18.948, 20.971, 22.499 and 23.831 and more preferably has characteristic peaks at 6.579, 6.708, 8.935, 9.145, 12,699, 13,450, 15,275, 16,934, 17,217, 18,123, 18,948, 20,186, 20,971, 22,499, 23,831, 26,139 and 29,589.
  10. 10. The crystalline form according to claim 9, wherein the powder X-ray diffraction pattern expressed using the diffraction angle 2θ is as shown in Fig. 11.
  11. 11. A method for producing a crystalline form according to claim 9 or 10, comprising dissolving a compound of formula 1 in a solvent V, adding an aqueous solution of p-toluenesulfonic acid and stirring the mixture, wherein the solvent V is selected from one of acetone, tetrahydrofuran, an acetone:propylene glycol methyl ether mixture (v/v=1:1), an acetone:propylene glycol methyl ether mixture (v/v=7:3) and an acetone:n-propanol mixture (v/v=7:3).
  12. 12. The crystalline form according to any one of claims 5, 6 and claims 9, 10, wherein the error range for 2θ is ±0.20.
  13. 13. A pharmaceutical composition comprising a pharmaceutically acceptable salt of 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one according to any one of claims 1, 2, 4 and 8 or a crystalline form according to any one of claims 5, 6 and claims 9, 10 and optionally a pharmaceutically acceptable excipient.
  14. 14. A method for producing a pharmaceutical composition comprising the step of mixing a pharmaceutically acceptable salt of 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one according to any one of claims 1, 2, 4 and 8 or a crystalline form according to any one of claims 5, 6 and claims 9, 10 with a pharmaceutically acceptable excipient.
  15. 15. Use of a pharmaceutically acceptable salt of 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one according to any one of claims 1, 2, 4 and 8, or a crystalline form according to any one of claims 5, 6 and claims 9, 10, or a pharmaceutical composition according to claim 13 in the preparation of an HER2 inhibitor.
  16. 16. The use of a pharmaceutically acceptable salt of 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one according to any one of claims 1, 2, 4 and 8, or a crystalline form according to any one of claims 5, 6 and claims 9, 10, or a pharmaceutical composition according to claim 13 in the preparation of a medicinal product for the treatment and/or prevention of cancer.