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Novel FLT3 kinase inhibitor and synthesis and application thereof

A kinase inhibitor and a novel technology, applied in the field of novel FLT3 kinase inhibitor and its synthesis and application, can solve problems such as inability to cope with intensive chemotherapy regimens, and achieve the effects of low price and simple synthesis method

Pending Publication Date: 2021-12-31
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While younger patients can achieve a cure rate of 35-40%, for older patients, they are often unable to cope with intensive chemotherapy regimens

Method used

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  • Novel FLT3 kinase inhibitor and synthesis and application thereof
  • Novel FLT3 kinase inhibitor and synthesis and application thereof
  • Novel FLT3 kinase inhibitor and synthesis and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] The name of the compound synthesized in this example is 1-(4-(4-amino-3-(4-(m-tolyloxy)phenyl)-1H-indazol-1-yl)-3-methylphenyl) -3-(5-(tert-butyl)isoxazol-3-yl)urea, its structural formula is as follows:

[0068]

[0069] Step a: (7g, 40.46mmol) p-bromophenol, (5.43g, 44.51mmol) 3-methylphenylboronic acid and (10g, 39.38mmol) diboronic acid pinacol ester (divaleroyl diboron) were added to 100ml Add (8.08g, 44.51mmol) copper acetate and (4.91g, 48.55mmol) triethylamine to 1,2-dichloroethane solvent, and react at room temperature under nitrogen protection for 24h; the reaction mixture is filtered through diatomaceous earth. The filtrate was concentrated in vacuo to give a residue, which was purified by chromatography on silica gel, eluting with 5% by volume ethyl acetate (EtOAc) in hexanes. (12g, 122.27mmol) Potassium acetate, (2.96g, 4.05mmol) 72287-26-4 (i.e. 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (PdCl 2 (dppf))), solvent 100ml DMF, 15h, 100°C (rea...

Embodiment 2

[0081] The name of the compound synthesized in this example is 1-(4-(4-amino-3-(4-(3-isopropylphenoxy)phenyl)-1H-indazol-1-yl)phenyl)- 3-(5-(tert-butyl)isoxazol-3-yl)urea, its structural formula is:

[0082]

[0083] Step a: Add (5.8g33.52mmol) p-bromophenol, (6g 36.88mmol) 3-isopropylphenylboronic acid and (9.36g, 36.88mmol) biboronic acid pinacol ester to 100ml 1,2-dichloroethyl Add appropriate amount of (6.7g, 36.88mmol) copper acetate and (4g, 40.23mmol) triethylamine to the alkane solvent, and react at room temperature under nitrogen protection for 24h; the reaction mixture is filtered through diatomaceous earth. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography eluting with 5% by volume EtOAc in hexanes. (9.87g, 100.57mmol) potassium acetate, (3g, 4.21mmol) 72287-26-4, solvent 100ml DMF, 15h, 100°C. The mixture was then passed through a short column of silica gel to remove insoluble material. The solvent was th...

Embodiment 3

[0088] The name of the compound synthesized in this example is 1-(4-(4-amino-3-(4-(m-tolyloxy)phenyl)-1H-indazol-1-yl)-3-methylphenyl) -3-(5-(tert-butyl)isoxazol-3-yl)urea, its structural formula is:

[0089]

[0090] Step a: 7g of p-bromophenol, 6g of 3-methylphenylboronic acid and 11.3g of pinacol diborate were added to 100ml of 1,2-dichloroethane solvent, and then an appropriate amount of copper acetate and triethylamine were added. Under the protection of nitrogen, the reaction was carried out at room temperature for 24 hours; the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography eluting with 5% by volume EtOAc in hexanes. 11.91g potassium acetate, 2.98g 72287-26-4, solvent 100ml DMF, 15h, 100°C. The mixture was then passed through a short column of silica gel to remove insoluble material. The solvent was then removed under reduced pressure to afford a cru...

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Abstract

The invention relates to a novel FLT3 kinase inhibitor and synthesis and application thereof, the structural formula of the inhibitor is shown in the specification, wherein the R1, R2, R3 and R4 are respectively and independently one of H, C1-C10 alkyl, C1-C10 alkoxy or halogen. Compared with Quizartinib, the inhibitor synthesized by the invention has the advantages that the IC50 value is in the same order of magnitude or even lower than that of Quizartinib, and the inhibitor can be used for preparing medicines for treating acute myelogenous leukemia.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to a novel FLT3 kinase inhibitor and its synthesis and application. Background technique [0002] Leukemia is a malignant disease mainly due to the abnormal proliferation of a certain series of white blood cells, which extensively infiltrate various tissues and organs in the body, resulting in bleeding, anemia, infection and infiltration. Acute myeloid leukemia (AML) is a debilitating disease that affects children and the elderly. With an estimated incidence of more than 19,520, it is the most common hematologic malignancy. AML is mainly characterized by abnormal proliferation of primitive and immature myeloid cells in bone marrow and peripheral blood. The clinical manifestations are anemia, hemorrhage, infection and fever, visceral infiltration, and metabolic abnormalities. Treatment is often life-threatening. The disease accounts for 30% of childhood leukemia. Childre...

Claims

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Application Information

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IPC IPC(8): C07D413/12A61K31/422A61P35/02
CPCC07D413/12A61P35/02
Inventor 汪忠华张莫轩杨茂成吴中山朱冉冉吴范宏王祥聪胡银杰李云芳
Owner SHANGHAI INST OF TECH
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