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Side chain protected aminoamido n-hexanoyl carboline carboxylic acid benzyl ester, preparation, activity and applications thereof

A technology of aminoamido and tert-butoxycarbonylaminoamido, which is applied in organic chemistry, drug combination, antitumor drugs, etc., and can solve problems such as unsatisfactory antitumor effects

Active Publication Date: 2019-06-21
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventor is dissatisfied with the minimum effective dose of 0.2 μmol / kg for this type of bis-indole alcohol amino acid benzyl ester to exert anti-tumor effect

Method used

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  • Side chain protected aminoamido n-hexanoyl carboline carboxylic acid benzyl ester, preparation, activity and applications thereof
  • Side chain protected aminoamido n-hexanoyl carboline carboxylic acid benzyl ester, preparation, activity and applications thereof
  • Side chain protected aminoamido n-hexanoyl carboline carboxylic acid benzyl ester, preparation, activity and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1 Preparation of (3S)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid benzyl ester (1)

[0018] Slowly add 1.5 mL of concentrated H to 300 mL of water in an ice bath 2 SO 4 , stirred for 3min. Then 5.00 g (15.1 mmol) of L-tryptophan benzyl ester hydrochloride and 6 mL of formaldehyde solution (40%) were added. Stir at room temperature for 72h, TLC showed that L-tryptophan benzyl ester hydrochloride disappeared. The pH of the reaction solution was adjusted to 7 with concentrated ammonia water under an ice bath, and filtered. The filter cake was dissolved with 100 mL of ethyl acetate, and the resulting solution was washed with saturated aqueous sodium chloride solution (40 mL×3), and then dried over anhydrous sodium sulfate. Filter and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=90:1) to obtain 1.9 g (41%) of the title compound as a yellow oily solid. ESI-MS(m / e): 30...

Embodiment 2

[0019] Embodiment 2 prepares 6-tert-butoxycarbonylaminocaproic acid (2)

[0020] 5.00 g (38.2 mmol) of 6-aminocaproic acid (EACA) were suspended in 50 mL of distilled water. Add 10 mL of aqueous sodium hydroxide solution (2M) to the obtained suspension under ice-cooling, and stir until dissolved. Add 9.2g (42.2 mmol) (Boc) to the resulting solution 2 A solution of O and 20 mL of dioxane was adjusted to pH 9 with aqueous sodium hydroxide solution (2M), and stirred for 30 min. Remove the ice bath and stir at room temperature until TLC shows that 6-aminocaproic acid disappears. The reaction solution was washed with saturated KHSO under ice bath 4 The aqueous solution was adjusted to pH 7, and concentrated under reduced pressure to remove dioxane. The reaction solution was washed with saturated KHSO under ice bath 4 The aqueous solution was adjusted to pH 2 and extracted with ethyl acetate (50 mL×3). The ethyl acetate layer was washed with saturated NaCl aqueous solution (40...

Embodiment 3

[0021] Example 3 Preparation of (3S)-N-(6-tert-butoxycarbonylamino n-hexanoyl)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid benzyl ester (3)

[0022] Dissolve 4.15g (18mmol) tert-butoxycarbonyl-6-aminocaproic acid in 80mL of anhydrous THF, add 2.46g (18.2mmol) N-hydroxybenzotriazole (HOBt) and 4.04g (19.6mmol ) N,N-dicyclohexylcarbodiimide (DCC), stirred for 60 minutes. Afterwards, a solution of 5.06 g (16.5 mmol) (3S)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid benzyl ester and 80 mL of anhydrous tetrahydrofuran was added to the obtained reaction liquid. The reaction mixture was adjusted to pH 9 with N-methylmorpholine (NMM) in an ice bath, and stirred at room temperature for 24 hours. TLC showed the disappearance of benzyl (3S)-2,3,4,9-tetrahydro-β-carboline-3-carboxylate. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was sequentially washed with saturated NaH...

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Abstract

The invention discloses (3S)-N-(6-aminoamido-n-hexanoyl)-2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester having the following structure (AA in the formula is selected from L-Asp (OBzl) residue, L-Glu (OBzl) residue and L-Arg (NO2) residue), a preparation method and antitumor applications thereof, and further relates to applications in preparation of antitumor drugs.

Description

technical field [0001] The present invention relates to (3S)-N-(6-aminoamido n-hexanoyl)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid benzyl ester (in the formula AA is selected from L-Asp (OBzl), L-Glu(OBzl) and L-Arg(NO 2 )Residues). It relates to their preparation method and anti-tumor effect, and relates to their application in the preparation of anti-tumor effect drugs. The invention belongs to the field of biomedicine. [0002] [0003] technical background [0004] Malignant tumors seriously threaten human health. Lung cancer is one of the most aggressive human cancers. For patients with advanced lung cancer, usually 10%-15% of them can only survive for 5 years. This difficult situation has not improved significantly over the past 30 years. In many clinical cases, lung cancer has metastasized to surrounding tissues before being diagnosed. Tumor metastasis, especially tumor lung metastasis is the greatest risk of death in cancer patients. So far, there is...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61P35/00
Inventor 赵明彭师奇丰华
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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