Nitrogen-containing heterocyclic compound or salt thereof

A compound and heterocyclic technology, applied in the direction of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc.

Active Publication Date: 2014-12-24
FUJIFILM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In normal bone marrow, the expression of FLT3 is limited to early precursor cells, but in blood cancer, the expression of FLT3 at a high concentration or the mutation of FLT3 contributes to the proliferation and deterioration of cancer through the activation of the above-mentioned signaling pathway

Method used

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  • Nitrogen-containing heterocyclic compound or salt thereof
  • Nitrogen-containing heterocyclic compound or salt thereof
  • Nitrogen-containing heterocyclic compound or salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0844] (1)

[0845] [chemical formula 45]

[0846]

[0847] To a solution of 11.6 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate in 100 mL of tetrahydrofuran, 8.4 mL of triethylamine and 5.1 mL of propylamine were added under ice-cooling, and stirred at room temperature for 30 minute. A 1.0 mol / L aqueous hydrochloric acid solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain oily 2-(methylthio)-4-( Propylamino)pyrimidine-5-carboxylic acid ethyl ester (A1) 11.7g.

[0848] 1 H-NMR (CDCl 3 )δ: 8.61 (1H, s), 8.27 (1H, brs), 4.32 (2H, q, J=7.0Hz), 3.55-3.48 (2H, m), 2.53 (3H, s), 1.73-1.60 (2H , m), 1.37(3H, t, J=7.3Hz), 0.99(3H, t, J=7.6Hz).

[0849] (2)

[0850] [chemical formula 46]

[0851]

[0852] In a s...

Embodiment 2

[0884] (1)

[0885] [chemical formula 53]

[0886]

[0887] 302 mg of N-(3-aminophenyl)-2,2,2-trifluoro-N-methylacetamide, 4-(propylamino)-2-((2- (Pyridin-4-yl) ethyl) amino) pyrimidine-5-carboxylic acid (A3) 627mg, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride 545mg and 1 Add 15 mL of N,N-dimethylformamide and 766 μL of triethylamine to 377 mg of -hydroxybenzotriazole monohydrate at room temperature, seal the reaction vessel, and stir at 100°C for 40 minutes using a microwave reactor . After cooling the reaction mixture to room temperature, it was added to saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: 97-96% ethyl acetate / methanol) to give 4-(propylamino)-2-((2-(pyridin-4-yl )ethyl)amino)-N-(3-(2,2,2-trifluoro-N-methylacetamide)phenyl)pyri...

Embodiment 3

[0907] Compounds (1-3) to (1-12) were obtained by the same method as in Example 1(7) or Example 1(8).

[0908] Table 16

[0909]

[0910] Table 17

[0911]

[0912] Table 18

[0913]

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PUM

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Abstract

The present invention addresses the problem of providing an Fms-like tyrosine kinase 3 (FLT3) inhibitor that is useful as a therapeutic agent for acute myeloid leukemia (AML). Provided is a novel nitrogen-containing heterocyclic compound represented by general formula [1] or a salt thereof. The compound according to the present invention or a salt thereof is usable as the active ingredient of a medicinal composition for treating diseases or conditions relating to FLT3 such as AML and acute promyelocytic leukemia (APL).

Description

technical field [0001] The present invention relates to nitrogen-containing heterocyclic compounds or salts thereof useful as Fms-like tyrosine kinase 3 inhibitors. Background technique [0002] Fms-like tyrosine kinase 3 (FLT3) is a type III protein belonging to receptor-type tyrosine kinases, with five immunoglobulin-like motifs (immnunoglobulin-like motifs) in the N-terminal extracellular domain and a C-terminal 2 kinase domains. FLT3 is expressed in normal CD34-positive human bone marrow precursor cells and dendritic progenitor cells, and plays an important role in the proliferation and differentiation of these cells (Non-Patent Document 1). In addition, the ligand (FL) of FLT3 is expressed in bone marrow mesenchymal cells and T cells, which affects the production of most cells of the hematopoietic system, and at the same time stimulates stem cells, precursor cells, and tree cells through interaction with other growth factors. One of the cytokines for the proliferation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/74A61K31/505A61K31/506A61K31/5377A61K31/55A61K31/551A61P35/02A61P43/00C07D239/48C07D239/49C07D401/12C07D401/14C07D403/12C07D405/12C07D409/12
CPCC07D213/74C07D239/48C07D239/49C07D401/06C07D401/12C07D401/14C07D403/04C07D403/12C07D403/14C07D405/12C07D409/12C07D413/04C07D413/12C07D413/14C07D417/12C07D471/04A61P35/00A61P35/02A61P43/00A61K31/505A61K31/506A61K31/5377A61K31/55A61K31/551C07D239/42C07D239/46A61K31/44
Inventor 高崎优辻野俊明田名部真太郎大洼恵佐藤公彦平井敦寺田大介井贯晋辅水本真介
Owner FUJIFILM CORP
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