Salt of benzoylaminopyridine derivative and application thereof in medicines

A technology of medicine and pharmacy, applied in the field of medicine, can solve the problems of undisclosed compound crystal structure and undisclosed crystal form, and achieve the effect of convenient long-term storage and placement

Active Publication Date: 2019-12-17
GUANGZHOU ANYANREN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, none of these patent applications discloses the crystal structure of the compou

Method used

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  • Salt of benzoylaminopyridine derivative and application thereof in medicines
  • Salt of benzoylaminopyridine derivative and application thereof in medicines
  • Salt of benzoylaminopyridine derivative and application thereof in medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Example 1 Citrate Crystal Form I

[0085] 1. Preparation of citrate crystal form I

[0086] The compound 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4 ]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (51mg, 0.116mmol) was added to acetone (1.0mL), beaten at 60°C for 1 hour, then added lemon A solution of acid (24.2mg, 0.126mmol) in acetone (1.0mL) was reacted for 7 hours; suction filtered, and the filter cake was vacuum-dried at room temperature overnight to obtain a white solid (73.2mg, 99.6%).

[0087] 2. Identification of citrate crystal form I

[0088] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, it has the following characteristic peaks expressed in angle 2θ: 5.20°, 8.72°, 9.35°, 10.43°, 10.86°, 11.84°, 12.50 °,13.62°,14.66°,15.24°,15.62°,16.40°,16.61°,17.35°,18.25°,18.78°,19.16°,19.54°,20.11°,20.98°,21.31°,21.80°,22.70°, 23.12°,23.63°,24.03°,24.87°,25.14°,25.56°,25....

Embodiment 2

[0090] Example 2 Citrate Amorphous

[0091] 1. Preparation of Amorphous Citrate

[0092] Compound 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2 ,4] Triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (51.8mg, 0.117mmol) was added into dichloromethane (1.0mL) and stirred to dissolve, then added A solution of citric acid (28.5 mg, 0.148 mmol) in acetone (1.0 mL) was reacted for about 7 hours; suction filtered, and the filter cake was vacuum-dried overnight at room temperature to obtain amorphous citrate (56.8 mg, 76.5%).

[0093] 2. Identification of Citrate Amorphous Form

[0094] Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, the experimental results are as follows figure 2 shown.

Embodiment 3

[0095] The pharmacokinetic experiment of embodiment 3 salts of the present invention

[0096] Get 8-12kg male Beagle dogs and divide them into 2 groups, 3 in each group, orally administer the capsules that test samples are housed, the dose is 5mg / kg, according to the time point 0.25,0.5,1.0,2.0,4.0,6.0,9.0 and 24h blood collection. A standard curve with an appropriate range was established according to the concentration of the sample, and the concentration of the test sample in the plasma sample was determined in the MRM mode using AB SCIEX API4000 LC-MS / MS, and quantitative analysis was performed. According to the drug concentration-time curve, the pharmacokinetic parameters were calculated by WinNonLin 6.3 software non-compartmental model method. See Table 1 for details.

[0097] Table 1 PK parameters of citrate crystal form I

[0098]

[0099] Experimental results:

[0100] As can be seen from Table 1, the citrates of the present invention all have better pharmacokin...

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Abstract

The invention relates to a salt of a benzoylaminopyridine derivative and application thereof in medicines, further relates to a pharmaceutical composition containing the salt or crystal form or a combination thereof, and application of the salt or the crystal form or the pharmaceutical composition in preparing the medicines for preventing, treating or relieving diseases regulated by ASK1 of patients.

Description

technical field [0001] The invention belongs to the field of medicines, and relates to salts of benzamidopyridine derivatives and their application in medicines, in particular to 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-( 6,7-Dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide The citrate and its application in medicine further relate to the crystal form of the citrate and the pharmaceutical composition comprising the citrate. The salt or the pharmaceutical composition is used for preventing, treating or alleviating diseases regulated by ASK1 in patients. Background technique [0002] Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase (MAP3Ks) family, also known as cell filament Mitogen-activated protein kinase kinase kinase 5 (mitogen-activated protein kinase kinase kinase 5, MAPKKK5, MAP3K5), consisting of 1375 amino acid residues, consists of 11 kinase subdomains and a molecule l...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07C59/265A61K31/4439A61P37/00A61P29/00A61P9/00A61P13/12A61P11/00A61P1/16A61P25/00
CPCA61P1/16A61P9/00A61P11/00A61P13/12A61P25/00A61P29/00A61P37/00C07C59/265C07D487/04
Inventor 谢德逊薛伟才戴洪果李永攀张辉
Owner GUANGZHOU ANYANREN PHARMA TECH CO LTD
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