Dipeptide modified 1-methyl-3-hydroxymethyl-tetrahydro-beta-carboline, synthesis and applications thereof

A technology of hydroxymethyl, boc-aa-val-obzl, applied in the preparation of anti-tumor drugs and P-selectin inhibitors, anti-tumor activity, the active field of inhibiting the expression of P-selectin, can solve the problem of P-selectin -Selectin is not inhibited etc.

Inactive Publication Date: 2018-12-11
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, they have no inhibitory effect on P-selectin

Method used

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  • Dipeptide modified 1-methyl-3-hydroxymethyl-tetrahydro-beta-carboline, synthesis and applications thereof
  • Dipeptide modified 1-methyl-3-hydroxymethyl-tetrahydro-beta-carboline, synthesis and applications thereof
  • Dipeptide modified 1-methyl-3-hydroxymethyl-tetrahydro-beta-carboline, synthesis and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1 Preparation of (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid

[0019] Slowly drop 0.2 mL of concentrated sulfuric acid (98%) into the suspension of 5.0 g (24.5 mmol) of L-tryptophan and 400 mL of distilled water. After ultrasonically dissolving everything, 4.5 mL (49.0 mmol) of acetaldehyde (40%) was added dropwise. The reaction mixture was stirred at room temperature for 12 h, adjusted to pH 7 with concentrated ammonia water, and allowed to stand for 1 h. The reaction mixture was filtered, the filter cake was thoroughly washed with distilled water, and dried to obtain 4.51 g (80%) of the title compound as a colorless powder. ESI-MS(m / z):231[M+H] + ; 1 H NMR (300MHz, DMSO-d6): δ (ppm) = 10.99 (s, 1H), 9.18 (s, 1H), 7.44 (d, J = 7.5Hz, 1H), 7.33 (t, J = 8.0Hz, 1H),7.08(t,J=8.0Hz,1H),6.99(t,J=7.5Hz,1H),4.22(q,J=4.8Hz,1H),3.69(dd,,J=10.5Hz,J =5.0Hz, 1H), 3.14(dd, J=10.5Hz, J=2.4Hz, 1H), 2.83(ddd, J=10.5Hz, J=5.0Hz, J=2.4Hz, 1H), 1.38 (d, ...

Embodiment 2

[0020] Example 2 Preparation of (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester

[0021] Slowly drop 5mL of thionyl chloride into 100mL of methanol under ice-water bath and stir for 30min. Add 2.0 g (8.7 mmol) (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid to the resulting solution, and stir at room temperature for 14 h. Hydrogen chloride was removed under reduced pressure, and the reaction mixture was washed with saturated NaHCO 3 The pH of the aqueous solution was adjusted to 7. Let it stand fully, and dissolve the filtered precipitate with 100 mL of ethyl acetate. The resulting solution was sequentially washed with saturated NaHCO 3 Wash with aqueous solution (30mL×3) and saturated NaCl aqueous solution (30mL×3). Ethyl acetate phase with Na 2 SO 4 Dry for 8 h, filter, and concentrate the filtrate under reduced pressure to afford 1.35 g (65%) of the title compound. ESI-MS(m / z): 245[M+H] + ; IR (cm -1 ):3202,2970,2937...

Embodiment 3

[0022] Example 3 Preparation of (1S,3S)-1-methyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline

[0023] 1.0 g (4.10 mmol) of (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester was dissolved in 30 mL of anhydrous tetrahydrofuran. 0.15 g (12.30 mmol) lithium aluminum hydride was added to the solution within 50 min under an ice-water bath. The reaction mixture was stirred at room temperature for 4 h, quenched by adding 0.5 mL aqueous sodium hydroxide solution (10%) and stirring at room temperature for 1 h. Filter and wash the filter cake repeatedly with anhydrous tetrahydrofuran. The collected filtrates were concentrated under reduced pressure to afford 0.50 g (48%) of the title compound. ESI-MS(m / z):217[M+H] + ; IR (cm -1 ):3202,2970,2937,2452,1750,1682,1559,1500,1457,1320,1237,1149,1015; 1 H NMR (300MHz, DMSO-d6): δ (ppm) = 10.72 (s, 1H), 7.34 (d, J = 7.8Hz, 1H), 7.28 (d, J = 7.8Hz, 1H), 7.01 (t, J=13.8Hz, 1H), 6.95(t, J=15.9Hz, 1H), 4.74(t, J...

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Abstract

The invention relates to dipeptide modified 1-methyl-3-hydroxymethyl-tetrahydro-beta-carboline, synthesis and applications thereof, and discloses (1S,3S)-1-methyl-3-(AA-Val-methoxy)-2,3,4,9-tetrahydro-beta-carboline represented by the following formula (AA is Gly residue, L-Ala residue, L-Leu residue, L-Ile residue, L-Pro residue, L-Phe residue, L-Val residue and L-Lys residue), a preparation method, antitumor activity and P-selectin expression inhibition activity thereof, such that the invention discloses applications of the (1S,3S)-1-methyl-3-(AA-Val-methoxy)-2,3,4,9-tetrahydro-beta-carboline in preparation of antitumor drugs and in P-selectin expression inhibitors. The formula is defined in the specification.

Description

technical field [0001] The present invention relates to (1S,3S)-1-methyl-3-(AA-Val-methoxy)-2,3,4,9-tetrahydro-β-carbolines of the following formula and their preparation methods , related to their anti-tumor activity, and further related to their activity of inhibiting the expression of P-selectin. Therefore the present invention relates to their application in the preparation of antitumor drugs and P-selectin inhibitors. The invention belongs to the field of biomedicine. Background technique [0002] P-selectin is highly expressed in various malignant tumors and is involved in the occurrence and development of various malignant tumors. Antineoplastic drugs targeting P-selectin are attracting more and more attention. The inventors have disclosed that the pentacyclic compound (the structure on the left side of the formula below) has antitumor activity at a dose of 0.1 μmol / kg / day. However, they have no inhibitory effect on P-selectin. Analysis of the structural features...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K31/437A61P35/00
CPCA61K31/437
Inventor 赵明彭师奇朱海梅肖静
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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