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Novel S-type or R-type tetrahydronaphthalene amide compounds and pharmaceutically acceptable salts thereof, and preparation method and application thereof

A technology of tetralinamide and compound, applied in the field of medicine, can solve problems such as death, adverse reactions of patients, steric hindrance and the like

Inactive Publication Date: 2019-11-19
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This is because the T315I mutation produces steric hindrance, which prevents the 3-hydroxy-phenylethyl group at the N-9 position of the purine in the inhibitor structure from binding to the hydrophobic pocket of ABL, but the FDA has currently terminated the use of Ponatinib, mainly because Ponatinib produces significant coagulation effects, leading to serious adverse reactions or death of patients

Method used

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  • Novel S-type or R-type tetrahydronaphthalene amide compounds and pharmaceutically acceptable salts thereof, and preparation method and application thereof
  • Novel S-type or R-type tetrahydronaphthalene amide compounds and pharmaceutically acceptable salts thereof, and preparation method and application thereof
  • Novel S-type or R-type tetrahydronaphthalene amide compounds and pharmaceutically acceptable salts thereof, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1: (S)-N-(3-(imidazo[1,2-b]pyridazin-3-ethynyl)-4-methylphenyl)-5-(4-methylpiperazine) Preparation of -5,6,7,8-tetrahydronaphthalene-2-carboxamide (compound 1)

[0109]

[0110] Step A: Synthesis of (S)-methyl 5-hydroxy-5,6,7,8-tetralin-2-carboxylate

[0111]

[0112] Put 10 ml of 1.0 M (R)-2-methyl-CBS-oxazoboridine (0.1 mmol) in a round-necked flask, add toluene to dissolve, lower to -10°C, add 25 ml of borane dimethyl Toluene solution of the complex compound of thioether (2 mmol) was slowly added dropwise with 40 ml of methyl 5-carbonyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate (5 g , 1 mmol), the dropwise addition was completed within half an hour, stirred for 1 h, added 20 ml of methanol and continued to stir at 0°C for 2 h. Rotary evaporation removed methanol, then extracted with 100 ml of ethyl acetate, the organic phase was washed with 1M phosphoric acid solution, water, saturated saline solution, dried over anhydrous sodium sulfate, filtered, ...

Embodiment 1-1

[0134] Example 1-1: (S)-N-(3-(imidazo[1,2-b]pyridazin-3-ethynyl)-4-methylphenyl)-5-(4-methylpiper Preparation of oxazin-1-yl)-5,6,7,8-tetralin-2-carboxamide hydrochloride (compound 1 hydrochloride)

[0135]

[0136] Add (S)-N-(3-(imidazo[1,2-b]pyridazin-3-ethynyl)-4-methylphenyl)-5-( 4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (506 mg, 1 mmol), hydrochloric acid (202 mg, 1.05 mmol), absolute ethanol 15 ml, warmed up to 80°C and refluxed and stirred for half an hour, then cooled naturally to room temperature, a solid precipitated, filtered, washed with 5 ml of cold ethanol, filtered, and recrystallized with absolute ethanol to obtain 558 mg of a white solid product, the yield 80%.

Embodiment 2

[0137] Example 2: (R)-N-(3-(imidazo[1,2-b]pyridazin-3-ethynyl)-4-methylphenyl)-5-(4-methylpiperazine- Preparation of 1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (compound 2):

[0138]

[0139] Step A: Synthesis of (R)-methyl 5-hydroxy-5,6,7,8-tetralin-2-carboxylate

[0140]

[0141] Referring to the method of embodiment 1 step A. Simply substituting (R)-2-methyl-CBS-oxazoborin (0.1 mmol) for (S)-2-methyl-CBS-oxazaborin (0.1 mol) afforded product 4.1 g, yielding The rate is 88.2%, and the ee value detected by chiral OD-H column is 98%. MS: m / z, 207.2 ([M+H] + )

[0142] Step B: Synthesis of (R)-methyl 5-chloro-5,6,7,8-tetralin-2-carboxylate

[0143]

[0144] Referring to the method of embodiment 1 step B. Just replace (S)-methyl 5-hydroxy-5,6,7,8-tetralin-2-carboxylate with (R)-5-hydroxy-5,6,7,8-tetralin- Methyl 2-carboxylate, 3.08 g of product was obtained, yield 92.6%. MS: m / z, 225.2 ([M+H] + )

[0145] Step C: Synthesis of (R)-methyl 5-(4-methylpiper...

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Abstract

The invention relates to novel S-type or R-type tetrahydronaphthalene amide compounds and pharmaceutically acceptable salts thereof, and a preparation method and application thereof. The novel S-typeor R-type tetrahydronaphthalene amide compounds and the pharmaceutically acceptable salts thereof have structures as shown in a general formula (I). The invention also provides the preparation methodfor the compounds, pharmaceutical combinations containing the compounds and antineoplastic action of the compounds. The novel substituted S-type or R-type tetrahydronaphthalene amide compounds have better anti-tumor activity and safety compared with control drugs, and can be used in the treatment of leukemia, gastrointestinal stromal tumors, lung cancer, colon cancer, ovarian cancer, kidney cancerand other tumors, so the therapeutic range of the compounds is wide, and the compounds are very valuable as an anti-tumor agent in the field of medicine.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a novel S-type or R-type tetrahydronaphthylamide compound which inhibits the growth of tumor cells and exerts an antitumor effect, a pharmaceutically acceptable salt thereof, a preparation method and an application thereof. Background technique [0002] Imatinib competitively inhibits the binding site between adenosine triphosphate (ATP) and thymidine kinase (TK) receptors such as KIT, blocks TK phosphorylation, thereby inhibiting signal transduction, and can inhibit KIT mutations related to kinase activity (causing KIT receptor activation) and wild-type KIT. There are three main targets: Abelson (ABL) protein, KIT protein and platelet-derived growth factor (PDGF) receptor. Imatinib reduces kinase phosphorylation in a GIST-derived cell line (GIST882) through gain-of-function KIT mutations that cause stem cell factor-independent activation, and completely inhibits kinase phosp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D471/04A61K31/5025A61K31/5377A61K31/496A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D471/04C07D487/04
Inventor 陈烨刘举丁实史建涛李军刘雨彤李杰张娇娇宫益林
Owner LIAONING UNIVERSITY
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