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Azaspiro compound and its preparation method and application
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A technology for azaspirocyclic compounds, which is applied in the field of azaspirocyclic compounds and their preparation, and can solve the problem of high concentration of LPA
Active Publication Date: 2021-04-16
GUANGZHOU HENOVCOM BIOSCI CO LTD
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Abstract
Description
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Problems solved by technology
In many pathological conditions, especially in tumor cells, ATX is highly expressed, resulting in excessive LPA concentration
Method used
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Embodiment 1
[0120] Compound 1: Preparation of tert-butyl 3,5-dichlorobenzyl 6-(4-sulfamoylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.
[0121]
[0122]
[0123] Synthesis according to the above route, including the following steps:
[0124] (1) Preparation of methyl 1-benzoylazetidine-3-carboxylate (compound 1-1).
[0125]Get a 250mL single-necked bottle, add azetidine-3-carboxylate methyl ester (10g, 86.9mmol), dissolve in DCM (100mL), add triethylamine (14.5mL, 104.2mmol, 1.2 equivalents), place in 0 ℃, slowly added BzCl (11.1 mL, 95.6 mmol, 1.1 equiv), stirred at room temperature overnight, followed by TLC monitoring. After completion of the reaction, cool to room temperature, add saturated NaHCO 3 The solution was extracted with DCM, washed with saturated brine, dried over anhydroussodiumsulfate, spin-dried, and passed through a column to obtain 18.5 g of a yellow liquid with a yield of 96.8%. ESI-MS m / z: 220.1(M+H) + .
[0126] (2) Preparation of dimethyl 1-benzoy...
Embodiment 2
[0149] Compound 2: Preparation of 4-(trifluoromethoxy)benzyl-6-(4-sulfamoylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.
[0150]
[0151] Synthesis according to the above route, including the following steps:
[0152] The compound 4-trifluoromethoxybenzyl alcohol (50mg, 0.26mmol, 1eq), N,N'-carbonyldiimidazole (51mg, 0.31mmol, 1.2eq) was dissolved in DMF in a 10mL single-necked bottle, and stirred at room temperature for 2h. Compound 1-9 was dissolved in DMF, TEA (46 μL, 0.31 mmol, 1.2 eq) was added, the reaction solution was added, and stirred at room temperature. TLC tracking monitoring. Spin off most of the solvent with an oil pump, add EA and water, wash with saturated brine, dry over anhydroussodiumsulfate, and pass through a column (DCM:acetone=3:1). 45 mg of white powder was obtained, namely Compound 2.
[0153] The characterization data of this compound 2 are: 1 H NMR (400MHz, DMSO-d 6 ,δ ppm ): 7.89(d, J=6.4Hz, 2H), 7.78(d, J=6.4Hz, 2H), 7.49(d, J=9.2...
Embodiment 3
[0155] Compound 3: Preparation of 3,5-dichlorobenzyl-2-(4-sulfamoylbenzoyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate.
[0156]
[0157]
[0158] Synthesis according to the above route, including the following steps:
[0159] (1) Preparation of methyl 1-benzoylpiperidine-4-carboxylate (compound 2-1).
[0160] Take a 100mL single-necked bottle, add p-methylpiperidine (5.1g, 35.6mmol), dissolve in DCM (50mL), add triethylamine (6mL, 42.7mmo, 11.2 equivalents), place at 0°C, and slowly add BzCl (4.5mL, 39.2mmol, 1.1eq), stirred at room temperature overnight, followed by TLC monitoring. After completion of the reaction, cool to room temperature, add saturated NaHCO 3 The solution was extracted with DCM, washed with saturated brine, dried over anhydroussodiumsulfate, spin-dried, and passed through a column to obtain 8.6 g of a yellow liquid with a yield of 98%. ESI-MS m / z: 248.1(M+H) + .
[0161] (2) Preparation of methyl 1-benzoylpiperidine-4,4-dicarboxylate (compound 2...
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Abstract
The invention discloses an azaspiro compound, a preparation method and application thereof, and belongs to the field of medicinal chemistry. The azaspiro compound with the structural characteristics of formula I of the present invention or its pharmaceutically acceptable salt or stereoisomer or solvate or prodrug can be combined with Autotaxin and used as an Autotaxin inhibitor, and then can be applied to prevent and treatment of diseases with pathological features characterized by increased Autotaxin expression, such as cancer, fibrotic diseases, especially pulmonary fibrosis and liver fibrosis, metabolic diseases, myelodysplastic syndromes, cardiovascular diseases, autoimmune diseases, inflammation, Nervous systemdisease or pain etc. Compared with single inhibitors, this series of compounds can block and interfere with the upstream of various key signaling pathways, reduce or delay the growth and metastasis of tumor cells, avoid premature drug resistance, and at the same time provide a new possibilities.
Description
technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to an azaspiro compound, a preparation method and application thereof. Background technique [0002] Autotaxin (ATX), as a unique extracellularenzyme, is part of the seven exonucleotide pyrophosphatase / phosphodiesterase family, also known as exonucleotide pyrophosphatase / phosphodiesterase 2 , used to catalyze the hydrolysis of lysophosphatidylcholine (LPC) to generate lysophosphatidic acid (LPA) with various biological activities. LPA is not only the precursor of phospholipid synthesis, but also can cause a wide range of biological effects through various signal transduction pathways. Once LPA is produced, it can pass through six cell surface specific receptor proteins (LPA 1-6 ), that is, G protein-coupled receptors (GPCRs) mediate their effects. Named after endothelial cell differentiation gene (Edg) and ventricular zone gene, LPA 1-6 They are LPA1 / Edg-2 / VZG-1, LP...
Claims
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