S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application

A compound and pharmaceutical technology, applied in the field of medicine, can solve problems such as life-threatening and serious conditions of patients, and achieve the effect of wide therapeutic window, broad anti-cancer spectrum, excellent anti-tumor activity and safety

Inactive Publication Date: 2012-07-25
陈烨 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in some patients, the conditi

Method used

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  • S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application
  • S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application
  • S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0090] Example 1: (S)-N-{4-methyl-3-[(4-pyridin-3-yl)pyrimidine-2-amino]phenyl}-5-(4-methylpiperazin-1-yl ) Preparation of-5,6,7,8-tetrahydronaphthalene-2-amide

[0091]

[0092] Step A: Synthesis of (S)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester

[0093]

[0094] Add 1 ml of 1.0M (R)-2-methyl-CBS-oxazoborane (1 mmol) toluene solution and 10 ml of borane-N,N-diethylaniline complex ( 10.5 mmol) toluene solution, heat the mixed solution to 30°C, and slowly add 30 ml of methyl 5-carbonyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate (2.04 G, 10 mmol), the addition was completed within half an hour. After stirring at 30°C for 2 hours, it was cooled to room temperature. 5 ml of methanol solution was added to the reaction solution. After stirring for 10 minutes, 15 ml of 1N aqueous hydrochloric acid was slowly added to the mixture. Stir for 20 minutes, then extract with 100 ml of ether, and wash the organic phase with 1N dilute hydrochloric acid, water, and sa...

Example Embodiment

[0105] Example 2: (R)-N-{4-methyl-3-[(4-pyridin-3-yl)pyrimidine-2-amino]phenyl}-5-(4-methylpiperazin-1-yl ) Preparation of-5,6,7,8-tetrahydronaphthalene-2-amide

[0106]

[0107] Step A: Synthesis of (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester

[0108]

[0109] Dissolve 5-carbonyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (3.06 g, 15 mmol) in 20 ml of tetrahydrofuran solution, add active Molecular sieve 5 grams, N 2 Under protection, slowly add 1.5 ml 1.0M (S)-2-methyl-CBS-oxazoborane (1.5 mmol) toluene solution at -20℃, and then add borane dimethyl sulfide complex (1.14 g, 15 mmol) in 5 ml of dry tetrahydrofuran solution, after 20 minutes of dripping, stir at -15~20°C for 1 hour. The solution is carefully quenched with 20 ml of methanol solution, and it is raised to room temperature to continue stirring. 12 After hours, the product was separated by reduced-price vacuum drying column chromatography to obtain 1.92 g of product with...

Example Embodiment

[0120] Example 3 (S)-N-{4-methyl-3-[(4-pyridin-3-yl)pyrimidine-2-amino]phenyl}-5-(3-methylimidazolidine-1-yl) -Synthesis of 5,6,7,8-tetrahydronaphthalene-2-amide

[0121]

[0122] Step A: Synthesis of 1-methylimidazolidine

[0123]

[0124] N-methylethylenediamine (1 g, 13.5 mmol) was added to formaldehyde (0.4 g, 13.5 mmol), potassium carbonate (6.4 g, 47.2 mmol), magnesium sulfate (5.6 g, 47.2 mmol) 25 In milliliter of chloroform suspension, stirred at room temperature for 18 hours, filtered, the filtrate was concentrated under reduced pressure, and purified by neutral alumina column chromatography under the condition of dichloromethane: methanol = 9:1 to obtain 0.81 g of 1-methylimidazolidine. The yield was 70%, MS(M+1)=87.11.

[0125] Step B: Synthesis of (S)-5-(3-methylimidazolidine-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester

[0126]

[0127] Dissolve (S)-5-chloro-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (2.41 g, 10 mmol) in 20 ml of ...

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Abstract

The invention relates to a novel compound R1 represented by general formula I. The compound R1 is an S-type or R-type tetrahydro-naphthalene amides compound, or a pharmaceutically acceptable salt or pro-drug of the compound, and is used as an antitumor drug. The invention also provides a preparation method of the compound, and a pharmaceutical composition containing the compound, and an antitumor research in vitro. The antitumor drug R1 obtained by the invention is the S-type or R-type tetrahydronaphthalene amides compound, is better in antitumor activity and safety and can be applied to treating tumors such as leukemia, lung cancer, liver cancer, colon cancer and ovarian cancer, so that the therapeutic window is wide, and the compound as an antitumor agent in the medicine field is very valuable.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to tetrahydronaphthalene amide compounds and pharmaceutically acceptable salts or prodrugs thereof which inhibit tumor cell growth and exert antitumor effects, as well as their preparation method and application. 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 phosphorylation at ...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D239/42A61K31/506A61P35/00A61P35/02
Inventor 陈烨王洋林小琳
Owner 陈烨
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