Salt of benzoylaminopyridine derivative and application thereof in medicines

A technology of medicine and pharmacy, applied in the field of crystal forms and pharmaceutical compositions containing the fumarate salt, can solve the problems of undisclosed compound crystal structure, no disclosure, etc., 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, these patent applications did not disclose the crystal structure of the compound, nor did it disclose its pharmaceutically acceptable salt

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

[0081] Example 1 Fumarate Crystal Form I

[0082] 1. Preparation of fumarate crystal form I

[0083] 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 (51.0mg, 0.115mmol) was added to ethanol (1.0mL), beaten for 15 minutes, then added A solution of fumaric acid (18.5 mg, 0.158 mmol) in ethanol (1.0 mL) was reacted for 7 hours; suction filtered, and the filter cake was vacuum-dried overnight at room temperature to obtain a white solid (58.2 mg, 90.4%).

[0084] 2. Identification of fumarate crystal form I

[0085] (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: 4.06°, 9.46°, 10.10°, 11.05°, 11.45°, 11.69°, 12.25 °,13.69°,14.03°,15.24°,15.62°,16.15°,16.89°,17.77°,18.68°,19.02°,19.54°,20.53°,21.22°,22.25°,22.58°,22.81°,23.40°, 23.86°,24.17°,24.71°,25.02°,25.82°,26.10...

Embodiment 2

[0087] The pharmacokinetic experiment of embodiment 2 salt of the present invention

[0088] 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.

[0089] Table 1 PK parameters of fumarate salt form I

[0090] Test sample Dose (mg / kg) AUClast(h*ng / ml) Cmax(ng / ml) Tmax(h) Fumarate Form I 5 23300 4620 1.17

[0091] Expe...

Embodiment 3

[0093] Embodiment 3 Stability experiment of the salt of the present invention

[0094] (1) High temperature experiment : Take an appropriate amount of the test sample and put it into a flat weighing bottle, spread it into a thin layer with a thickness of ≤5mm, place it at a temperature of 60°C for 10 days, take a sample on the 5th and 10th day, observe the color change of the sample, and test the purity of the sample by HPLC.

[0095] (2) High humidity experiment : Take an appropriate amount of a batch of test products and put them into a flat weighing bottle, spread them into a thin layer with a thickness of ≤5mm, place them for 10 days at 25°C and RH 90%±5%, take samples on the 5th and 10th days, and observe the samples The color changes, and the purity of the sample is tested by HPLC.

[0096] Experimental results:

[0097] Under the conditions of high temperature (60°C) and high humidity (25°C, RH 90%±5%), the appearance and purity of the salt of the present invention...

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PUM

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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 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 fumarate and its application in medicine further relate to the crystal form of the fumarate and the pharmaceutical composition comprising the fumarate. 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 molecul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P37/06A61P29/00A61P9/00A61P13/12A61P11/00A61P1/16A61P25/28A61P3/10A61P3/00A61K31/4439
CPCA61P1/16A61P3/00A61P3/10A61P9/00A61P11/00A61P13/12A61P25/28A61P29/00A61P37/06C07B2200/13C07D487/04
Inventor 谢德逊李永攀李权伟覃健耀戴洪果
Owner GUANGZHOU ANYANREN PHARMA TECH CO LTD
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