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Amino-acid ester derivative and application thereof

A technology of alkylation and drugs, which is applied in the direction of drug combination, organic chemistry, antineoplastic drugs, etc.

Pending Publication Date: 2022-07-19
NEURODAWN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Sodium dichloroacetate (DCA) is used as a specific PDK1 inhibitor for the treatment of malignant tumors, but long-term use of this drug can cause clinical side effects such as peripheral neurotoxicity

Method used

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  • Amino-acid ester derivative and application thereof
  • Amino-acid ester derivative and application thereof
  • Amino-acid ester derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Synthesis of Compound P1

[0024]

[0025] SM1 (500mg, 2.15mmol), potassium carbonate (653mg, 4.73mmol), 30ml DMF were added to a reaction flask with a U-shaped drying tube, stirred at room temperature for 1h, and then iodomethane (1.5g, 10.75mmol) was added, TLC detected that the reaction was complete, 20 ml of water and 20 ml of ethyl acetate were added, and the liquids were separated by stirring. The ethyl acetate phase was retained, washed with saturated NaCl aqueous solution, and anhydrous Na 2 SO 4 Drying, filtration, rotary evaporation, and silica gel column chromatography of the crude product (ethyl acetate:petroleum ether=10:1) yielded 220 mg of yellow oil, with a yield of 42%. ESI-MS: 244.15 [M+H] + .

[0026] 1H NMR (400 MHz, DMSO-d 6 ) δ 7.89 (d, J = 7.7 Hz, 1H), 4.11 (t, J =7.7 Hz, 1H), 3.63 (s, 3H), 2.08 (s, 4H), 1.27 (d, J = 5.0 Hz, 6H) ), 0.88 (dd,J = 8.1, 6.9 Hz, 6H).

Embodiment 2

[0027] Example 2: Synthesis of Compound P2

[0028]

[0029] Add SM1 (500mg, 2.15mmol), potassium carbonate (653mg, 4.73mmol), 30ml DMF to a reaction flask with a U-shaped drying tube, stir at room temperature for 1h, then add iodomethane (305mg, 3.15mmol), TLC Detection, the reaction is complete, add 20 ml of water and 20 ml of ethyl acetate, stir and separate the liquid, retain the ethyl acetate phase, wash with saturated NaCl aqueous solution, and anhydrous Na 2 SO 4 Drying, filtration, rotary evaporation, and the crude product was subjected to silica gel column chromatography (ethyl acetate: petroleum ether=10:1) to obtain 276 mg of yellow oil, yield 56%. ESI-MS: 230.28 [M+H] + .

[0030] 1H NMR (400 MHz, DMSO-d 6 ) 8.56 (dd, J = 20.0, 7.9 Hz, 1H), 4.20 (ddd, J = 15.7, 8.1, 6.2 Hz, 1H), 3.66 (d, J = 5.2 Hz, 3H), 3.33 – 3.28 (m, 1H), 2.10 (dd, J = 10.5, 4.1 Hz, 4H), 1.10 (dd, J = 6.9, 3.9 Hz, 3H), 0.97 –0.82 (m, 6H).

Embodiment 3

[0031] Example 3: Synthesis of Compound P3

[0032]

[0033] SM1 (500mg, 2.32mmol), potassium carbonate (652mg, 4.73mmol), 30ml DMF were added to a reaction flask with a U-shaped drying tube, stirred at room temperature for 1h, and then 1,2-dibromoethane (525mg) was added. , 2.79 mmol), TLC detection, the reaction is complete, add 20 ml of water and 20 ml of ethyl acetate, stir and separate the liquids, retain the ethyl acetate phase, wash with saturated NaCl aqueous solution, anhydrous Na 2 SO 4 Drying, filtration, rotary evaporation, the crude product was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 10:1) to obtain 320 mg of yellow oil, yield 57%. ESI-MS: 242.29 [M+H] + .

[0034] 1H NMR (400 MHz, CDCl 3 ) δ 9.36 (d, J = 6.8 Hz, 1H), 4.49 (dd, J =8.0, 5.0 Hz, 1H), 3.74(s, 3H), 2.23 (m, 1H), 2.01 (s, 3H), 1.90 – 1.82 (m, 2H), 1.59 – 1.51 (m, 2H), 0.99 (dd, J = 6.9, 1.9 Hz, 6H).

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PUM

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Abstract

The invention discloses an amino-acid ester derivative compound as well as a pharmaceutical composition and application thereof. The amino-acid ester derivative provided by the invention has PDK1 inhibitory activity, and the compound has a wide application prospect in preparation of antitumor drugs.

Description

technical field [0001] The invention belongs to the field of pharmacy, and provides a class of amino acid ester compounds, a preparation method and pharmaceutical use thereof. The compounds can inhibit the activity of PDK1 and have application prospects for preparing antitumor drugs. Background technique [0002] Malignant tumor is a common and frequently-occurring disease that seriously threatens human life, and its mortality is second only to cardiovascular disease. According to estimates by the World Health Organization, more than 5 million people die from malignant tumors in the world every year, and 10 million new malignant tumor patients are discovered every year. In recent years, although tumor chemotherapy has made considerable progress, the treatment of solid tumors, which are the most serious threat to human life and health, accounting for more than 90% of malignant tumors, has not achieved satisfactory results. At present, the drug treatment of tumors is mainly t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/12A61P35/00
CPCC07C235/12A61P35/00C07C2601/02C07C2601/04C07C2601/08C07C2601/14
Inventor 李福龙方芳安文吉张正平陈荣杨士豹
Owner NEURODAWN PHARM CO LTD
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