Crystallization of azabicyclic compounds

A technology of crystallization and pharmaceutical composition, applied in the field of crystallization, to achieve excellent oral absorbability and high stability

Active Publication Date: 2020-01-10
TAIHO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] On the other hand, in general, in a pharmaceutical composition for oral administration, in addition to the stability of the active ingredient, excellent absorbability at the time of oral administration is also required, and Patent Documents 1 and 2 do not mention Compound 1 at all. Crystals, and descriptions of the stability and oral absorbability of the crystals

Method used

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  • Crystallization of azabicyclic compounds
  • Crystallization of azabicyclic compounds
  • Crystallization of azabicyclic compounds

Examples

Experimental program
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Embodiment

[0062] Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples at all. Although the present invention has been described in detail using examples, it will be understood by those skilled in the art that various changes and modifications can be made. Therefore, as long as such changes or modifications do not depart from the scope of the present invention, they are also included in the scope of the present invention.

[0063] Unless otherwise specified, various reagents used in the examples were commercially available. The NMR spectrum uses AL400 (400MHz, Japan Electronics (JEOL)), Mercury400 (400MHz, Agilent Thechnologies) spectrometer, or an Inova 400 (400MHz, Agilent Thechnologies) spectrometer equipped with a 400M NMR probe (Protasis), in a deuterated solvent When tetramethylsilane is contained, measurement is performed using tetramethylsilane as an internal standard, and ot...

Embodiment 1

[0104] Example 1 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)- Synthesis of Type II Crystal of 1H-Imidazol-1-yl)-1H-Pyrazolo[3,4-b]pyridin-1-yl}benzamide

[0105] 3-Ethyl-4-{3-isopropyl-4-(4-(1-methyl Base-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide as a white solid (4.0 g) was added into acetone (19.54 mL), and stirred under reflux for 16 hours. After cooling to room temperature, the solid was collected by filtration, washed with acetone (8.4 mL), and then dried under reduced pressure at 70-80° C. for 16-24 hours to obtain type II crystals (yield: 1.59 g, yield: 57.0%, purity 98.37%).

[0106] In addition, type II crystals such as figure 2 Diffraction angles (2θ) 7.7°, 8.0°, 11.1°, 12.5°, 12.9°, 14.2°, 15.2°, 15.8°, 17.2°, 17.7°, 19.0°, 20.2° are shown in the powder X-ray diffraction pattern , 21.1°, 22.5°, 22.8°, 23.5°, 24.5°, 26.1°, 26.7°, 27.4°, 28.0°, 28.7°, 29.4°, 30.0°, 31.7°, 35.1°, 36.2°, 36.9°, and 37.6 ° characteri...

Embodiment 2

[0108] Example 2 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)- Synthesis of Type II Crystal of 1H-Imidazol-1-yl)-1H-Pyrazolo[3,4-b]pyridin-1-yl}benzamide

[0109] 3-Ethyl-4-{3-isopropyl-4-(4-(1-methyl A white solid (400 mg) of 1-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide was added to methyl ethyl ketone (2.8 mL), and stirred under reflux for 16 hours. After cooling to room temperature, the solid was collected by filtration, washed with methyl ethyl ketone (1.2 mL), and then dried under reduced pressure at 70-80°C for 16-24 hours to obtain type II crystals (yield: 197 mg, yield: 60.9%, Purity 98.83%).

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Abstract

The invention provides a 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H -Pyrazolo[3,4-b]pyridin-1-yl}benzamide is a stable crystal with excellent oral absorbability. 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyridine of the present invention Type II crystal of azolo[3,4-b]pyridin-1-yl}benzamide, characterized in that, in the powder X-ray diffraction pattern, it has a diffraction angle (2θ±0.2°) of 7.7°, 8.0° , 11.1°, 12.5°, 12.9°, 15.2°, 15.8°, 17.2°, 19.0°, 22.5°, 26.1° and 27.4° at least three or more characteristic peaks.

Description

technical field [0001] The present invention relates to a novel crystal of an azabicyclic compound which is stable, has excellent oral absorbability, and is useful as an antitumor agent. Background technique [0002] In general, when a compound is used as an active ingredient of a pharmaceutical, chemical stability and physical stability of the compound are required in order to maintain stable quality and / or facilitate storage and management. Therefore, it is preferable to obtain a compound in a stable crystal form, and generally, there are many precedents for selecting the most stable crystal form as a drug substance for pharmaceuticals. [0003] At present, various HSP90 inhibitors have been reported as antitumor agents. In Patent Documents 1 and 2, 3-ethyl-4-{3 -Isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridine-1 -yl}benzamide (hereinafter also referred to as "compound 1"). [0004] On the other hand, in general, in a pharmaceutical...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/4439A61P35/00A61P43/00
CPCA61K31/4439C07D471/04A61P35/00A61K31/437C07B2200/13
Inventor 宇野贵夫
Owner TAIHO PHARMA CO LTD
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