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Novel crystal of (3S)-3-[2-(6-amino-2-fluoropyridine-3-yl)-4-fluoro-1h-imidazole-5-yl]-7-[5-chloro-2-(1h-tetrazole-1-yl)phenyl]-2,3-dihydroindolizine-5(1H)-one

A technology of indolinazine and fluoropyridine, applied in (3S)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl Novel crystal field of ]-7-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]-2,3-dihydroindorazin-5(1H)-one capable of resolving bleeding complications Symptoms are the problem, the drug does not show sufficient antithrombotic effect, etc.

Pending Publication Date: 2021-08-06
ONO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although conventional anticoagulants exhibit excellent antithrombotic effects, bleeding complications, which are serious side effects, remain problematic
Alternatively, in order not to cause bleeding complications, the dose of the agent is limited, and it is presumed that there is a possibility that the agent does not exhibit a sufficient antithrombotic effect

Method used

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  • Novel crystal of (3S)-3-[2-(6-amino-2-fluoropyridine-3-yl)-4-fluoro-1h-imidazole-5-yl]-7-[5-chloro-2-(1h-tetrazole-1-yl)phenyl]-2,3-dihydroindolizine-5(1H)-one
  • Novel crystal of (3S)-3-[2-(6-amino-2-fluoropyridine-3-yl)-4-fluoro-1h-imidazole-5-yl]-7-[5-chloro-2-(1h-tetrazole-1-yl)phenyl]-2,3-dihydroindolizine-5(1H)-one
  • Novel crystal of (3S)-3-[2-(6-amino-2-fluoropyridine-3-yl)-4-fluoro-1h-imidazole-5-yl]-7-[5-chloro-2-(1h-tetrazole-1-yl)phenyl]-2,3-dihydroindolizine-5(1H)-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0169] The present invention will be described in detail by referring to the following examples, but the present invention is not limited to the examples.

[0170] Regarding chromatographic separation or TLC, solvents in parentheses correspond to employed elution solvents or developing solvents, and ratios are expressed by volume ratios.

[0171] Regarding NMR, solvents in parentheses correspond to solvents used for measurement.

[0172] Compound names used in this specification are usually named according to IUPAC rules using the computer program ACD / Name (registered trademark) given by Advanced Chemistry Development, or by IUPAC nomenclature.

[0173] The measurement times, solvents and column conditions used for LC / MS analysis in the following examples are shown below. At the same time, t R Indicates the retention time.

[0174] Condition a. Column YMC-Triart C18, 2.0mm×30mm, 1.9μm; column temperature 30°C; mobile phase (liquid A) 0.1% trifluoroacetic acid aqueous soluti...

Embodiment 1

[0177] Example 1(1): 6-fluoro-5-iodo-2-pyridinamine

[0178] Under ice cooling, N-iodosuccinimide (56.5 g) was added in multiple portions (3 parts) to 6-fluoro-2-pyridinamine (25.6 g) in N,N-dimethylformamide (200 mL ) in the solution. The mixture was stirred at room temperature for 3 hours, and tap water (0.5 L) was added to the reaction solution. The mixture was extracted 3 times with ethyl acetate / hexane (1 / 1, 300 mL), and the organic layer was washed with saturated aqueous sulfurous acid (0.5 L), saturated aqueous sodium carbonate (0.5 L, twice), tap water (0.5 L ) and saturated brine (0.5 L), dried, and concentrated. To the obtained residue was added hexane / ethyl acetate (3 / 1, 150 mL), and the slurry was washed at room temperature, and filtered. The obtained solid was dried to obtain the title compound (36.7 g) having the following physical properties.

[0179] TLC: Rf 0.56 (ethyl acetate:hexane=1:2).

[0180] Example 1(2): Bis(2-methyl-2-propenyl)(6-fluoro-5-iod...

Embodiment 2

[0240] Example 2: (3R)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro- 2-(1H-tetrazol-1-yl)phenyl]-2,3-indolinazin-5(1H)-one-3,5-dihydroxybenzoic acid (2 / 1)

[0241] To the compound of Example 1(13) (20 mg) were added 3,5-dihydroxybenzoic acid (2.83 mg) and acetonitrile (100 μL). The resulting mixture was stirred at 25°C for 1 day to obtain a precipitate. The precipitate was filtered off, and then dried in air to obtain a crystal of the title compound having the following physical property values.

[0242] 1 H-NMR (DMSO-d6): 11.70, 9.65, 9.13, 7.86-7.75, 7.14-7.13, 6.96-6.92, 6.78-6.75, 6.40-6.36, 6.00, 5.92, 5.71, 5.68, 3.32, 3.20-2.93, 2.27 -2.20.

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Abstract

Provided is a novel crystalline form of (3S)-3-[2-(6-amino-2-fluoropyridine-3-yl)-4-fluoro-1h-imidazole-5-yl]-7-[5-chloro-2-(1h-tetrazole-1-yl)phenyl]-2,3-dihydroindolizine-5(1h)-one. Provided is (3S)-3-[2-(6-amino-2-fluoropyridine-3-yl)-4-fluoro-1h-imidazole-5-yl]-7-[5-chloro-2-(1h-tetrazole-1-yl)phenyl]-2,3-dihydroindolizine-5(1h)-one-3-hydroxy benzoic acid (1 / 1).

Description

technical field [0001] The present invention relates to (3S)-3-[2-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2-( Novel crystals of 1H-tetrazol-1-yl)phenyl]-2,3-indolinazin-5(1H)-one and others. Background technique [0002] Thrombosis and thromboembolism as its complication (hereinafter referred to as thromboembolic disease) are ranked as a high-ranking cause of death in adults together with cancer, and have become an important problem in recent years. Thromboembolic diseases occur through the formation of thrombus at the site of vascular injury. Alternatively, thromboembolic disease occurs when a thrombus is released and carried by the bloodstream into another blood vessel where the thrombus blocks that vessel. Thromboembolic diseases include, for example, venous thromboembolism, which is a general term for deep vein thrombosis and pulmonary embolism, stroke, angina pectoris, myocardial infarction, various other arterial and venous thrombosis, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/444A61P7/02A61P9/00C07D471/04
CPCA61P7/02A61P9/00C07D471/04A61K47/38A61K9/2054A61K9/2013A61K9/0019A61K47/26A61K9/0095A61K31/444A61P9/10C07B2200/13
Inventor 藤户贵之小野静香大谷修平
Owner ONO PHARMA CO LTD