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3-(2-amino-ethyl)-alkylidene)-thiazolidine-2,4-dione and 1-(2-amino-ethyl)-alkylidene-1,3-dihydro-indol-2-one derivatives as selective sphingosine kinase 2 inhibitors

a technology of alkylidene and thiazolidine, which is applied in the field of 3-(2-amino-ethyl)-alkylidene-1,3-dihydroindol-2-one derivatives as selective sphingosine kinase 2 inhibitors, can solve the problem of scarce selective sphk2 inhibitors and achieve the effect of high concentration

Inactive Publication Date: 2015-01-01
VIRGINIA COMMONWEALTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes the development of new compounds that can selectively inhibit the activity of a protein called SphK2. These compounds have been found to be effective in treating cancer and other diseases. The patent also describes methods for using these compounds to treat cancer in patients. The new compounds are designed to target SphK2 and are believed to have potential as therapeutic agents for human diseases.

Problems solved by technology

Even though several pan SphK inhibitors and SphK1 selective inhibitors have been developed and tested in preclinical experiments, selective SphK2 inhibitors remain scarce.

Method used

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  • 3-(2-amino-ethyl)-alkylidene)-thiazolidine-2,4-dione and 1-(2-amino-ethyl)-alkylidene-1,3-dihydro-indol-2-one derivatives as selective sphingosine kinase 2 inhibitors
  • 3-(2-amino-ethyl)-alkylidene)-thiazolidine-2,4-dione and 1-(2-amino-ethyl)-alkylidene-1,3-dihydro-indol-2-one derivatives as selective sphingosine kinase 2 inhibitors
  • 3-(2-amino-ethyl)-alkylidene)-thiazolidine-2,4-dione and 1-(2-amino-ethyl)-alkylidene-1,3-dihydro-indol-2-one derivatives as selective sphingosine kinase 2 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Compound 26

[0080]To a stirred suspension of bromoethylamine hydrobromide 25 (20.5 g, 100 mmol), (Boc)2O (21.8 g, 100 mmol) in dichloromethane (200 mL) was added triethylamine (13.9 mL, 100 mmol) dropwise at 0° C., after added the mixture was stirred at room temperature (rt). overnight, water was added, the separated CH2Cl2 layer was washed with brine, and dried by Na2SO4, remove the solvent to give a colorless oil (20 g).

example 2

Preparation of Compound 27

[0081]A mixture of 2,4-thiazolidinedione (7.9 g, 68 mmol), compound 26 (17.9 g, 80 mmol), K2CO3 (11.1 g, 92 mmol), TBAI (2.5 g, 6.8 mmol) in acetone (100 mL) was stirred at 40° C. for 10 h, suction filter, the filtrate was concentrated under vacuum, the residue was purified by flash column chromatography (Hexane / EA=4 / 1 to 2 / 1) to give a white solid (12.3 g).

example 3

Preparation of Compounds 28-36

[0082]A solution of compound 27 (12 mmol), aldehyde (12 mmol) and piperidine (3.6 mmol) in MeOH (60 mL) was stirred at rt. overnight, remove solvent under vacuum, the residue was purified by flash column chromatography (Hexane / EA=8 / 1) to give a white solid, which was subject to Boc deprotection conditions in ethyl acetate (30 mL) by 4 M HCl in dioxane (15 mL), the solution to give 28-36 as white solid.

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Abstract

3-(2-amino-ethyl)-5-[3-(4-substituted-phenyl)-alkylidene)-thiazolidine-2,4-dione and 1-(2-amino-ethyl)-3-alkylidene-1,3-dihydro-indol-2-one and derivatives thereof are provided for use as selective SphK2 inhibitors and for use in the treatment of human diseases, such as cancer.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The invention generally relates to 5-alkylidenethiazolidine-2,4-dione and 3-alkylidene-1,3-dihydro-indol-2-one analogs and their use as selective sphingosine kinase 2 (SphK2) inhibitors in clinical implications. In particular, the invention provides 5-alkylidenethiazolidine-2,4-dione and 3-alkylidene-1,3-dihydro-indol-2-one analogs and derivatives thereof as SphK2 inhibitors and for use in the treatment of cancer.[0003]2. Background of the Invention[0004]Sphingosine-1-phosphate (S1P), a lipid metabolite, has been recognized and demonstrated as an important signaling mediator for vital cellular and physiological processes, such as cell motility, invasion, proliferation, angiogenesis and apoptosis. S1P is produced from sphingosine by two kinases, namely, sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2). Upon production, S1P is secreted and interacts with a family of G-protein coupled receptors (S1P1-5) on the...

Claims

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Application Information

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IPC IPC(8): C07D277/34
CPCC07D277/34C07D209/34A61P35/00
Inventor ZHANG, SHIJUNSPIEGEL, SARAH
Owner VIRGINIA COMMONWEALTH UNIV
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