ATX inhibitor as well as preparation method and application thereof

A technology of solvate and alkyl, which is applied in the field of ATX inhibitors and its preparation, can solve the problem of low inhibitory activity and achieve excellent drug efficacy, high inhibitory activity, and high clinical application prospects

Pending Publication Date: 2022-01-11
SUZHOU ARK BIOPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, although GLPG-1690 has inhibitory activity on ATX, its inhibitory activity is not very high. Therefore, more inhibitors with higher inhibitory activity on ATX still need to be developed

Method used

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  • ATX inhibitor as well as preparation method and application thereof
  • ATX inhibitor as well as preparation method and application thereof
  • ATX inhibitor as well as preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0111] The present invention also provides a typical synthetic method of the compound shown in the above formula I, to further describe the technical scheme of the present invention, the synthetic method comprises the following steps:

[0112] Step 1: Compound 1 reacts with the corresponding aldehyde and 1,1,3,3-tetramethylbutylisonitrile under the catalysis of magnesium chloride to generate intermediate 2;

[0113] Step 2: intermediate 2 is deprotected by heating in formic acid to obtain intermediate 3;

[0114] Step 3: Optionally, react intermediate 3 with the corresponding halogenated hydrocarbon to obtain intermediate 4 through nucleophilic substitution;

[0115] Step 4: intermediate 4 is hydrolyzed to obtain intermediate 5;

[0116] Step 5: intermediate 5 and intermediate 6 undergo a nucleophilic substitution reaction under alkaline conditions to obtain intermediate 7;

[0117] Among them, intermediate 6 is prepared by compound 11 through a two-step reaction: first, int...

Embodiment 1

[0195] 2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)imidazo[1,2-a ]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0196]

[0197] Step 1a: Preparation of 2-amino-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0198]

[0199] The specific method of step 1a: To a solution of 3-(4-fluorophenyl)-3-oxopropionitrile (6.0 g, 36.78 mmol) in ethanol (72 mL) was added pyridine (2.97 mL, 36.78 mmol) at room temperature. The mixture was stirred at 70°C for 15 minutes and then cooled to room temperature. A solution of thiourea (5.61 g, 73.56 mmol) and iodine (9.33 g, 6.78 mmol) in EtOH (36 mL) was then added dropwise slowly. After stirring at room temperature for one hour, 1M Na 2 S 2 o 3 (36 mL) to quench the reaction. After filtration, the filter cake was washed with water and dried to give 2-amino-4-(4-fluorophenyl)thiazole-5-carbonitrile (4.2 g) as a white solid.

[0200] Step 1b: Preparation of 2-chloro-4-(4-fluorophenyl)thiazole-5-...

Embodiment 2

[0228] 2-((2-ethyl-6-(6-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)pyridin-3-yl)imidazo[1, 2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0229]

[0230] Step 2a: Preparation of ethyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetate

[0231]

[0232] The specific method of step 2a: under nitrogen protection, add 2-(5-bromopyridin-2-yl) ethyl acetate (200mg, 0.82mmol), pinacol diborate (229mg, 0.90mmol), potassium acetate (120mg , 1.23 mmol) in 1,4-dioxane (2 mL) was added to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (58 mg, 0.08 mmol). The mixture was heated to 85°C and stirred for 2 hours, diluted with water (15 mL), and extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give brown oil 2-(5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborin-2-yl)pyridin-2-yl)ethyl acetate (171 mg).

[0233] ...

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Abstract

The invention provides an ATX inhibitor as well as a preparation method and application thereof. The ATX inhibitor is a compound with a structure shown in a formula I or pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label of the compound. Compared with an existing ATX inhibitor GLPG-1690, the ATX inhibitor disclosed by the invention has higher inhibition activity, and has excellent medicine effect, in-vitro / in-vivo pharmacokinetics and safety and a good clinical application prospect.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to an ATX inhibitor and a preparation method thereof. Background technique [0002] Autotaxin (ATX, also known as ENPP2 [exonucleotide pyrophosphatase / phosphodiesterase 2] or lysophospholipase D) is a member of the exonucleotide pyrophosphatase / phosphodiesterase (ENPP) family. ATX converts lysophosphatidylcholine (LPC) into biologically active lysophosphatidic acid (LPA). LPA consists of a glycerol chain, a phosphate group and a fatty acyl chain of different lengths and degrees of saturation. Once LPA is produced, it can exert its biological activity through the mediation of six specific receptor proteins (LPA1-6) on the cell surface, that is, G protein-coupled receptors. Many evidences show that ATX is the main source of LPA in blood. The ATX-LPA signaling pathway is involved in cell survival, migration, and proliferation, thereby having an important link with many...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/444A61K31/497A61P35/00A61P37/02A61P29/00A61P19/00A61P17/00A61P25/00A61P3/00A61P11/00A61P1/16A61P13/12
CPCC07D471/04A61P35/00A61P37/02A61P29/00A61P19/00A61P17/00A61P25/00A61P3/00A61P11/00A61P1/16A61P13/12
Inventor 彭程钱梦飞吕遐师武进尹伟刘奉友金羿邹罡袁海卿邬征
Owner SUZHOU ARK BIOPHARM CO LTD
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