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Pharmaceutically acceptable salt and crystal form of pyrrolo[2,3-d]pyridazin-7-one derivative and preparation method of medicinal salt and crystal form

A 3-d, medicinal salt technology, applied in the field of medicine and chemical industry, can solve problems such as crystal form research

Inactive Publication Date: 2020-08-07
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the patent does not conduct any research on the crystalline form of the compound and its salts

Method used

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  • Pharmaceutically acceptable salt and crystal form of pyrrolo[2,3-d]pyridazin-7-one derivative and preparation method of medicinal salt and crystal form
  • Pharmaceutically acceptable salt and crystal form of pyrrolo[2,3-d]pyridazin-7-one derivative and preparation method of medicinal salt and crystal form
  • Pharmaceutically acceptable salt and crystal form of pyrrolo[2,3-d]pyridazin-7-one derivative and preparation method of medicinal salt and crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1: Compound A hydrochloride

[0058] Prepare hydrogen chloride solution for later use: pipette 0.1ml of concentrated hydrochloric acid, add 9.9ml of ethanol and shake well to prepare ethanol hydrochloric acid solution for later use;

[0059] Weigh free compound A (100mg), add 5ml of n-hexane, add 1.8ml of ethanol hydrochloric acid solution, heat and stir at 50°C, filter, wash with n-hexane, and dry. The XRPD pattern of the crystalline product is shown in figure 1 , its characteristic peak positions are shown in Table 1 below, and there is an endothermic peak at 173.8°C in its DSC spectrum.

[0060] Table 1

[0061]

[0062]

[0063] Experiment 1: Stability Study

[0064] The crystal form I of compound A hydrochloride was placed flat to investigate the stability of the samples under different temperature or / and humidity conditions. The sampling inspection period was 7 days, 14 days and February. The specific data are shown in Table 2:

[0065] Table 2...

Embodiment 2

[0068] Embodiment 2: Compound A hydrochloride

[0069] Compound A (100 mg) was added to 5 ml of tetrahydrofuran solution, 18 ul of concentrated hydrochloric acid was added, heated and stirred at 50° C., filtered, washed with tetrahydrofuran, and dried to obtain a solid. It was detected as the I crystal form of hydrochloride by XRPD.

Embodiment 3

[0070] Example 3: Form II of Compound A

[0071] Add compound A hydrochloride (60mg) into 0.6ml of methanol solution, stir to dissolve, add 0.3ml of water, heat up to 25°C, then cool down to 5°C at a rate of 10K / min, stir and crystallize, filter, and dry at 50°C Obtain solid sample, this crystalline product XRPD collection of patterns sees figure 2 , and its characteristic peak positions are shown in Table 3 below.

[0072] table 3

[0073] Peak number 2θ value [° or degrees] Relative Strength% 1 5.855 100 2 6.310 26.5 3 7.030 47.6 4 8.404 5.4 5 11.755 62.3 6 12.835 17.9 7 14.280 47.4 8 16.311 7.7 9 17.525 24 10 17.925 18.4 11 20.090 17.4 12 21.445 20.6 13 23.130 25 14 25.285 26.3 15 25.890 19.4

[0074] After the chloride ion content test, it does not contain chloride ions.

[0075] DSC detection shows that the XRPD spectrum of the sample does not change during the ...

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Abstract

The invention provides a pharmaceutically acceptable salt and a crystal form of a pyrrolo[2,3-d]pyridazin-7-one derivative and a preparation method of the pharmaceutically acceptable salt and the crystal form. The invention specifically provides a BTK kinase inhibitor, namely (R)-4-amino-1-(1-(butyl-2-acetylenyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one salt, and a crystal form and a preparation method thereof. The preparation method comprises the steps of salt formation, dissolving, crystallizing and the like, and prepares the stable crystal form.

Description

technical field [0001] The application belongs to the technical field of medicine and chemical industry, and specifically relates to a BTK kinase inhibitor (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4- (2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one salt, its crystal form, and its preparation method. Background technique [0002] WO2016007185 discloses a compound (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy ) phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (compound of formula I), which is a novel BTK kinase inhibitor, which is selective in kinase, clinical Efficacy or indications and safety and other aspects have been improved. However, the patent does not conduct any studies on the crystalline form of the compound and its salts. [0003] [0004] Salt formation is one of the effective means to improve the physical and chemical properties of drug molecules and improve their druggability. It can change t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/00A61P37/02A61K31/5025
CPCA61K31/5025A61P35/00A61P37/02C07B2200/13C07D487/04
Inventor 周先强杜振兴王捷
Owner JIANGSU HENGRUI MEDICINE CO LTD
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