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 ve

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
Comparison scheme
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Example Embodiment

[0111] The present invention also provides the use of a compound of Formula typical synthesis shown in I, to further describe the technical solutions of the present invention, the synthetic method comprising the steps of:

[0112] Step 1: compound 1 with the corresponding aldehydes and 1,1,3,3-tetramethylbutyl isocyanide chloride catalytic reaction at intermediate 2;

[0113] Step 2: Intermediate 2 was heated in formic acid deprotection to give intermediate 3;

[0114] Step 3: optionally, a halogenated hydrocarbon to the corresponding intermediates 3 by a nucleophilic substitution reaction to give intermediate 4;

[0115] Step 4: Intermediate 4 by hydrolysis of Intermediate 5;

[0116] Step 5: Intermediate 5 Intermediate 6 under basic conditions to obtain a nucleophilic substitution reaction of intermediate 7;

[0117] Wherein the 6-step intermediate prepared by reacting compound 11: first with thiourea compound 11 by ring closure to afford intermediate 12; Intermediate 12 to give...

Example Embodiment

[0194] Example 1:

[0195] 2 - ((2-ethyl-6- (4- (2- (3-hydroxyazotylbutane-1-yl) -2-oxidant) phenyl) imidazole [1,2-a ] Pyridin-3-yl) (meth) amino) -4- (4-fluorophenyl) thiazole-5-methitrile

[0196]

[0197] Step 1A: Preparation 2-amino-4- (4-fluorophenyl) thiazole-5-methitrile

[0198]

[0199] Specific means of step 1a: pyridine (2.97 mL, 36.78 mmol) was added in an ethanol (72 ml) of 3- (4-fluorophenyl) -3-oxpropionitrile (6.0 g, 36.78 mmol) ethanol (72 mL). The mixture was stirred at 70 ° C for 15 minutes after cooling to room temperature. EtOAc (363 g, 73.56 mmol) was then slowly added dropwise. After stirring at room temperature for an hour, add 1M NA 2 S 2 O 3 (36 mL) quenched reaction. Filtration was washed with water, dried with water, dried the white solid 2-amino-4- (4-fluorophenyl) thiazole-5-methitrile (4.2 g).

[0200] Step 1B: Preparation 2-chloro-4- (4-fluorophenyl) thiazole-5-methitrile

[0201]

[0202] The specific method of step 1b: The nitrite tert-buty...

Example Embodiment

[0227] Example 2:

[0228] 2 - ((2-ethyl-6- (6- (2- (3-hydroxy-azetidin-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 2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) acetate

[0231]

[0232] DETAILED the step 2a: Under nitrogen, a solution of 2- (5-bromo-2-yl) acetate (200mg, 0.82mmol), with boronic acid pinacol ester (229mg, 0.90mmol), potassium acetate (120 mg of , 1.23mmol) in 1,4-dioxane (2mL) was added [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (58mg, 0.08mmol). The mixture was heated to 85 ℃ stirred for 2 hours, add water (15mL), and extracted with ethyl acetate (20mL × 2). The combined organic phase was washed with saturated brine (15mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown oil 2- (5- (4,4,5,5-tetramethyl-1,3,2 - dioxaborolan-2-yl) pyridin-2-yl) acetate (171mg).

[0233] B...

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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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