Tartrate salt of selective cdk9 inhibitor and its crystal form

A technology of tartrate salt and crystal form, which is applied in the field of chemical pharmacy, can solve the problems of unsalted species, further evaluation of performance, and unprepared, etc., and achieve good crystallinity, easy production scale expansion, and good stability. Effect

Active Publication Date: 2020-03-20
CHANGZHOU QIANHONG BIOPHARMA +1
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Problems solved by technology

[0009] The Chinese invention patent with the publication number CN103373994A (incorporated herein by reference in its entirety) discloses a class of compounds with CDK-9 inhibitory function and its preparation

Method used

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  • Tartrate salt of selective cdk9 inhibitor and its crystal form
  • Tartrate salt of selective cdk9 inhibitor and its crystal form
  • Tartrate salt of selective cdk9 inhibitor and its crystal form

Examples

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Example Embodiment

[0053] Example 1 3-(5-Fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-ylamino)-benzenesulfonamide (code named LS007) salt-forming properties

[0054] 1.1 High-throughput screening for salt formation

[0055] Combined with the pKa value of LS007 and its solubility in different pH, it can be determined that acids with a pKa value of about 3 or less can be used as the acid for salt formation screening. Therefore, we chose 8 acids: hydrochloric acid, sulfuric acid, aspartic acid, maleic acid, phosphoric acid, glutamic acid, tartaric acid, and fumaric acid.

[0056] After dissolving the drug, add it to a 96-well plate, and determine the volume of counter ion to be added according to the molar amount of drug added and the number of counter ion functional groups. The heating time and temperature can be determined according to the specific circumstances (generally 40°C, 1 hour). In order to ensure a certain pressure during the reaction in the bottle, the absolute tightness of th...

Example Embodiment

[0072] Example 2 3-(5-Fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-ylamino)-benzenesulfonamide tartrate crystal form

[0073] In this study, aiming at the polymorphism of LS007 tartrate, we used different crystallization conditions and experimental methods to systematically screen the possible crystal forms of compound LS007 tartrate. Through nearly 300 crystallization experiments, it is found that LS007 tartrate can exist in two different crystal forms, namely crystal forms A and B. Further characterization found that there is no significant difference in physical and chemical properties between different crystal forms. In the conversion experiment between crystal forms, it was found that Form A is more stable crystal form, and Form B can be transformed into Form A crystal form under certain conditions.

[0074] (1)Form A

[0075] Columnar crystals, the drug melts and decomposes, the peak temperature of decomposition is 236.8℃. It does not attract humidity (at 80% h...

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Abstract

The invention relates to the technical field of chemical pharmacy, and discloses a compound of 3-(5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-ylamino)-benzenesulfonamide Tartrate and its polymorphs, which are inhibitors of protein kinases, especially cyclin-dependent kinase 9 (CDK9), are useful in the treatment of proliferative disorders such as cancer and other diseases in which protein kinase/CDK activity is implicated.

Description

technical field [0001] The invention relates to the technical field of chemical pharmacy, in particular to 3-(5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-ylamino)-benzenesulfonate The salt form of the amide and its stable crystal form, which are selective inhibitors of cyclin-dependent kinases (CDK) such as CDK9, can be used for the treatment of cell proliferative diseases such as cancer. Background technique [0002] Proliferative diseases such as cancer are characterized by uncontrolled and deregulated cell proliferation. The protein kinase family is an important class of enzymes that has been the subject of extensive research in this regard. The protein kinase family is one of the largest in the human genome. Most kinases contain a catalytic domain of 250-300 amino acid residues with a conserved core structure. This domain contains the binding pocket for ATP, whose terminal phosphate group is covalently transferred to its macromolecular substrate. Pro...

Claims

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Application Information

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IPC IPC(8): C07D417/04A61K31/506A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D417/04C07B2200/13C07C59/255A61K31/506
Inventor 王淑东王辉江立群吕锦晨居文建
Owner CHANGZHOU QIANHONG BIOPHARMA
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