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KR-20260062874-A - Crystal Form of Free Base of Imidazo[1,2-a]pyridine Compound and Preparation Method Therefor

KR20260062874AKR 20260062874 AKR20260062874 AKR 20260062874AKR-20260062874-A

Abstract

The present invention relates to a crystalline form of an imidazo[1,2-a]pyridine compound, more specifically, an azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone, which is a raw material for pharmaceuticals and an intermediate for a final salt addition compound, and to a crystalline monohydrate form, crystalline form A and B and a method for preparing the same. The crystalline monohydrate form, crystalline form B and crystalline form A of the compound of Formula I according to the present invention have excellent stability under high humidity or high temperature conditions and can be usefully utilized in the formulation of pharmaceuticals.

Inventors

  • 전성현
  • 안정기
  • 김성화
  • 안성완

Assignees

  • 온코닉테라퓨틱스 주식회사
  • 제일약품주식회사

Dates

Publication Date
20260507
Application Date
20251028
Priority Date
20241029

Claims (20)

  1. Crystalline monohydrate form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the following chemical formula I: [Chemical Formula I]
  2. A monohydrate crystalline form according to claim 1, characterized in that the crystalline form comprises three or more diffraction peaks selected from the group consisting of 2θ values of the powder X-ray diffraction pattern of 24.607° (±0.2°), 16.978° (±0.2°), 12.254° (±0.2°), 9.773° (±0.2°), 8.739° (±0.2°), 11.113° (±0.2°), and 13.458° (±0.2°).
  3. A monohydrate crystalline form according to claim 2, further comprising at least one diffraction peak selected from the group consisting of 2θ values of the powder X-ray diffraction pattern of 22.989°(±0.2°), 22.365°(±0.2°), 17.785°(±0.2°), 25.528°(±0.2°), and 13.972°(±0.2°).
  4. A monohydrate crystalline form according to claim 1, characterized by having a differential scanning calorimetry (DSC) endothermic peak at 196.21℃ (±0.5℃) when the heating rate is 10℃/min.
  5. A monohydrate crystalline form according to claim 1, characterized in that the crystalline form has excellent stability under high humidity conditions of 60% to 90% relative humidity.
  6. A monohydrate crystalline form according to claim 1, characterized in that the crystalline form has excellent stability under high temperature conditions of 50°C to 100°C and high humidity conditions of 60% to 90% relative humidity.
  7. A monohydrate crystalline form according to claim 1, characterized in that the crystalline form is an azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone acid addition salt or an intermediate for use in preparing the crystalline form thereof.
  8. Crystalline form A of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the following chemical formula I: [Chemical Formula I]
  9. In claim 8, the crystalline form A is characterized in that the crystalline form comprises three or more diffraction peaks selected from the group consisting of 2θ values of the powder X-ray diffraction pattern of 7.319°(±0.2°), 9.219°(±0.2°), 13.777°(±0.2°), 18.541°(±0.2°), 26.062°(±0.2°), 20.434°(±0.2°), 22.255°(±0.2°), 11.649°(±0.2°), and 14.693°(±0.2°).
  10. Crystalline form A according to claim 9, further comprising at least one diffraction peak selected from the group consisting of 2θ values of the powder X-ray diffraction pattern of 12.353°(±0.2°), 27.519°(±0.2°), 26.751°(±0.2°), 23.443°(±0.2°), 12.757°(±0.2°), and 15.507°(±0.2°).
  11. Crystalline form A, characterized in that, in claim 8, it has a differential scanning calorimetry (DSC) endothermic peak at 195.95℃ (±0.5℃) when the heating rate is 10℃/min.
  12. In claim 8, the crystalline form A is characterized by having excellent stability under high temperature conditions of 50℃ to 100℃.
  13. Crystalline Form A according to claim 8, characterized in that the crystalline form is an azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone acid addition salt or an intermediate for use in preparing the crystalline form thereof.
  14. Crystalline form B of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the following chemical formula I: [Chemical Formula I]
  15. In claim 14, the crystalline form B is characterized in that the crystalline form comprises three or more diffraction peaks selected from the group consisting of 2θ values of the powder X-ray diffraction pattern of 10.539°(±0.2°), 13.727°(±0.2°), 7.071°(±0.2°), 25.776°(±0.2°), 15.022°(±0.2°), 22.273°(±0.2°), 28.266°(±0.2°), 20.515°(±0.2°), and 19.334°(±0.2°).
  16. Crystalline form B according to claim 15, further comprising at least one diffraction peak selected from the group consisting of 2θ values of the powder X-ray diffraction pattern of 21.146°(±0.2°), 24.931°(±0.2°), 24.123°(±0.2°), and 19.787°(±0.2°).
  17. Crystalline form B according to claim 14, characterized by having a differential scanning calorimetry (DSC) endothermic peak at 196.59℃ (±0.5℃) when the heating rate is 10℃/min.
  18. In claim 14, the crystalline form B is characterized by having excellent stability under high temperature conditions of 50°C to 100°C.
  19. Crystalline form B according to claim 14, characterized in that the crystalline form is azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone acid addition salt or an intermediate for use in preparing the crystalline form thereof.
  20. A method for preparing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone acid addition salt or a crystalline form thereof, comprising using the crystalline form of any one of claims 1 to 19 as an intermediate.

Description

Crystal Form of Free Base of Imidazo[1,2-a]pyridine Compound and Preparation Method Therefor The present invention relates to a crystalline form of an imidazo[1,2-a]pyridine compound and a method for preparing the same, and more specifically, to a monohydrate crystalline form, crystalline form A, crystalline form B of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone and a method for preparing the same. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone is a compound that exhibits gastric acid secretion inhibitory activity and can also be used as an intermediate of a final active pharmaceutical ingredient in the form of an acid addition salt for use as a pharmaceutical product. Gastrointestinal inflammatory diseases or acid-related diseases such as peptic ulcers, gastric and duodenal ulcers, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD) are the most common digestive diseases, affecting the majority of the world's population, including Korea. In order to address the problems of conventional proton pump inhibitors (PPIs), there has recently been increasing interest in and need for Potassium Competitive Acid Blockers (P - CABs, acid pump antagonists), which have a mechanism of inhibiting acid secretion by reversibly binding to the K+ binding site of H+/K+-ATPase and inhibiting potassium-competitive competition. In particular, unlike irreversible proton pump inhibitors (PPIs), reversible proton pump inhibitors (P-CABs) are expected to be very effective in improving nocturnal symptoms, which are a problem of irreversible proton pump inhibitors, as well as providing rapid efficacy through their mechanism and being easy to take regardless of whether it is before or after a meal. In this regard, Korean registered patent No. 10-1777971 discloses azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone as an imidazo[1,2-a]pyridine derivative, which is a P-CAB drug, and a method for manufacturing the same, and Korean registered patent No. 10-2496869 discloses azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate salt and a method for manufacturing the same. To ensure the safety of finished pharmaceutical products, the stability of active pharmaceutical ingredients (APIs) is critical; furthermore, to synthesize high-purity APIs, it is necessary to synthesize the final API from intermediate compounds that possess both high purity and stability. To this end, regulatory authorities require that when managing finished pharmaceutical products, they identify and control factors that may affect the product—such as the purity, impurities, and stability of each raw material—starting from the initial materials used for API synthesis, in addition to the API itself, which serves as the active ingredient. Recently, global atmospheric temperatures have been rising due to global warming, and climatic conditions are shifting toward extremes, such as dryness in some regions or high humidity caused by heavy rainfall. To ensure the safety of pharmaceuticals, it is crucial that active pharmaceutical ingredients (APIs) remain unaffected by these extreme weather conditions. Therefore, it is necessary to ensure high stability that is not affected by extreme weather conditions for azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone, which is an active active drug and used as an intermediate for the final salt addition compound. The development of compounds with improved purity and stability of such active drugs not only expands the formulation range of finished pharmaceutical products but also provides an opportunity to manufacture and store pharmaceutical compositions more easily. Accordingly, the inventors of the present invention made diligent research efforts to discover a form that possesses stability even under extreme climatic conditions, as a compound intended to be used as an active active pharmaceutical ingredient and as an intermediate for final salt addition compounds. As a result, the most stable crystalline form of the imidazo[1,2-a]pyridine compound was identified under respective humidity and harsh thermodynamic conditions, thereby completing the present invention. Figure 1 shows an X-ray powder diffraction (XRD) analysis of the crystalline form of the monohydrate of the compound of Formula I prepared according to Example 1 of the present invention. Figure 2 shows the thermogravimetric analysis (TGA) of the crystalline form of the monohydrate of the compound of Formula I prepared according to Example 1 of the present invention. Figure 3 shows a differential scanning calorimetry (DSC) analysis of the crystalline form of the monohydrate of the compound of Formula I prepared according to Example 1 of the present invention. Figure 4 shows an X-ray powder diffraction (XRD) analys