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Methods for treating patients with hematologic malignancies

A technology of malignant blood diseases and leukemia cells, which is applied in the field of treating patients with malignant blood diseases, and can solve the problems of poor survival and prognosis of cancer

Pending Publication Date: 2019-12-27
APTOSE BIOSCIENCES INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the survival prognosis of the cancer is poor

Method used

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  • Methods for treating patients with hematologic malignancies
  • Methods for treating patients with hematologic malignancies
  • Methods for treating patients with hematologic malignancies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0181] Example 1: Synthesis of 1-{3-fluoro-4-[7-(5-methyl-1H-imidazol-2-yl)-1-oxo-2,3-dihydro-1H-isoindole- 4-yl)-phenyl)-3-(2,4,6-trifluoro-phenyl)-urea (compound 7)

[0182]

[0183] 2,4,6-Trifluorobenzoic acid (0.08g, 0.45mmol) was dispersed in ether (5.7mL), and phosphorus pentachloride (PCl 5 , 0.11g, 0.52mmol), and then stirred for 1 hour. After the reaction was completed, the organic solvent was concentrated under reduced pressure below room temperature, and then the reaction solution was diluted by adding acetone (3.8 mL). Subsequently, sodium azide (NaN) dissolved in water (0.28 mL) at 0°C 3 , 0.035g, 0.545mmol) was slowly added dropwise to the reaction solution. After stirring for 2 hours at room temperature, the 2,4,6-trifluorobenzoyl azide thus formed was diluted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, dispersed in THF (2mL), and added containing 4-(4-amino-2-fluorophenyl)-7-(5-methyl-1H-imida...

Embodiment 2

[0184] Example 2: Binding constant of compound 7 to wild-type and mutant FLT3 kinase

[0185] The measurement of the kinase activity is called the binding constant or K d value. The scheme used to obtain these values ​​is described accordingly. For most assays, a kinase-tagged T7 phage strain was prepared in an E. coli host derived from the BL21 strain. Escherichia coli was grown to log phase and infected with T7 phage and incubated at 32°C with shaking until dissolved. The lysate is centrifuged and filtered to remove cell debris. The remaining kinases are produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. The streptavidin-coated magnetic beads were treated with a biotinylated small molecule ligand at room temperature for 30 minutes to generate an affinity resin for kinase assay. Block the ligandized beads with excess biotin and wash with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligands and allow non-s...

Embodiment 3

[0190] Example 3: Western blot analysis of compound 7 in the case of MV4-11 cells

[0191] figure 1 Shows the results of Western blot analysis. Without being bound by any theory, this proves that compound 7 inhibits the FLT3 pathway in MV4-11 cells.

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PUM

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Abstract

The present disclosure comprises a method for administering 2,3-dihydro-isoindole-1-one compound or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, for the treatment of hematological cancers such as acute myeloid leukemia (AML). The present disclosure further relates to reducing or inhibiting cell-proliferation which is activated by wild-type or mutated Fms-like tyrosinekinase-3 receptor (FLT3). The present disclosure further relates to a method of inhibiting or reducing abnormal (e.g., overexpressed) wild-type or mutated BTK activity or expression in a subject in need thereof.

Description

[0001] Cross references to related applications [0002] This application claims priority to the U.S. Provisional Application No. 62 / 461,584 filed on February 21, 2017 and the U.S. Provisional Application No. 62 / 578,948 filed on October 30, 2017. The disclosure of the U.S. Provisional Application is based on this All purposes are incorporated herein by reference in their entirety. Technical field [0003] The present invention relates to 2,3-dihydro-isoindol-1-one compounds or pharmaceutically acceptable salts, esters, prodrugs, hydrates, solvates and isomers thereof for the treatment of cancers such as blood cancers , Where the patient exhibits FLT3 mutations or wild-type or mutant forms of BTK. [0004] Background of the invention [0005] Many tyrosine kinases have been shown to be part of regulatory pathways that promote cell survival in many cancer types. The Fms-like tyrosine kinase 3 (FLT3) gene is one such example that encodes a membrane-bound receptor tyrosine kinase that a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10A61K45/06A61K31/4178
CPCC07D403/04A61K31/4178A61P35/02
Inventor W·G·莱斯J·M·曹Y·洪
Owner APTOSE BIOSCIENCES INC
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