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Dipeptide and tripeptide proteasome inhibitors as well as preparation method and pharmaceutical application thereof

A compound and stereoisomer technology, applied in the fields of dipeptide and tripeptide proteasome inhibitors and their preparation methods and pharmaceutical applications, can solve toxic and side effects, non-covalent proteasome inhibitors have less research, Insufficient drug safety and other issues

Active Publication Date: 2015-10-14
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the two drugs already on the market are both covalent proteasome inhibitors, the covalent binding mode may lead to serious toxic side effects, and there are deficiencies in drug safety, while non-covalent binding proteasome inhibitors are expected to overcome the above-mentioned Therefore, it is of great significance to find new non-covalent proteasome inhibitors
[0003] At present, there are few studies on non-covalent proteasome inhibitors

Method used

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  • Dipeptide and tripeptide proteasome inhibitors as well as preparation method and pharmaceutical application thereof
  • Dipeptide and tripeptide proteasome inhibitors as well as preparation method and pharmaceutical application thereof
  • Dipeptide and tripeptide proteasome inhibitors as well as preparation method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0166] Example 1: WK-3-18

[0167]

[0168] a)

[0169] Dissolve 2.1 g of white solid Boc-Asn-Val-OH (6.3 mmol) in 50 mL of DMF, add 1.2 g of 2-hydroxy-4-methoxybenzylamine hydrochloride (6.3 mmol), 2.4 g of HATU (6.3 mmol), respectively, 2.0 g DIEA (15.75 mmol). Stir overnight at room temperature, TLC detection, the reaction is complete, evaporate the solvent under reduced pressure, dissolve with ethyl acetate, wash with 1mol / L hydrochloric acid solution, saturated sodium carbonate solution, saturated sodium chloride solution, and the remaining organic layer is washed with After drying over sodium sulfate, the solvent was evaporated under reduced pressure, washed with a small amount of ethyl acetate, and filtered to obtain 2.5 g of a white solid with a yield of 85%.

[0170] b)

[0171] Dissolve the white solid (0.57 mmol) obtained in 266 mg1a in 8 mL of dichloromethane, add 2 mL of trifluoroacetic acid, stir at room temperature for 2 hours, TLC detects that the reactio...

Embodiment 2

[0172] Example 2: WK-3-21

[0173]

[0174] Dissolve the white solid (0.43 mmol) obtained in 200 mg1a in 8 mL of dichloromethane, add 2 mL of trifluoroacetic acid, stir at room temperature for 2 hours, TLC detects that the reaction is complete, evaporate the solvent under reduced pressure to obtain a white solid, dissolve it in In 20 mL of DMF, 75 mg of 3-indoleacetic acid (0.43 mmol), 164 mg of HATU (0.43 mmol), and 139 mg of DIEA (0.57 mmol) were added, respectively. Stir at room temperature overnight, TLC detection, the reaction is complete, the solvent is evaporated under reduced pressure, and after being partially dissolved with ethyl acetate, the solution is washed with 1mol / L hydrochloric acid solution, saturated sodium carbonate solution, saturated sodium chloride solution, distilled water, and evaporated under reduced pressure. Dry, wash with ethyl acetate, and filter to obtain 142 mg of a light red solid with a yield of 63%. mp:214℃-215℃. 1 H-NMR (CD 3 OD)δ7.48...

Embodiment 3

[0175] Example 3: WK-3-24

[0176]

[0177] Dissolve the white solid (0.43 mmol) obtained in 200 mg1a in 8 mL of dichloromethane, add 2 mL of trifluoroacetic acid, stir at room temperature for 2 hours, TLC detects that the reaction is complete, evaporate the solvent under reduced pressure to obtain a white solid, dissolve it in 91 mg of 4-felbinac (0.43 mmol), 164 mg of HATU (0.43 mmol), and 139 mg of DIEA (0.57 mmol) were added to 20 mL of DMF, respectively. Stir at room temperature overnight, TLC detection, the reaction is complete, the solvent is evaporated under reduced pressure, and after being partially dissolved with ethyl acetate, the solution is washed with 1mol / L hydrochloric acid solution, saturated sodium carbonate solution, saturated sodium chloride solution, distilled water, and evaporated under reduced pressure. Dry, wash with ethyl acetate, filter and recrystallize from methanol to obtain 105 mg of white solid with a yield of 43.6%. mp:231℃-232℃. 1 H-NMR (...

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Abstract

The invention discloses new dipeptide and tripeptide compounds shown in formulas I and II as well as stereoisomers and physiologically acceptable salt thereof, a preparation method of the compounds, a pharmaceutical preparation containing the compounds and a clinical application of the compounds in treatment of proteasome-related diseases.

Description

technical field [0001] The present invention relates to novel dipeptide and tripeptide compounds of general formulas I and II, as well as their stereoisomers and physiologically acceptable salts. The use of these compounds in the treatment of proteasome-related diseases also relates to their treatment methods and pharmaceutical compositions containing the compounds. Background technique [0002] The ubiquitin-proteasome pathway is the main pathway of protein degradation in eukaryotic cells, and plays an important role in the processes of cell division, differentiation, growth and development, signal transduction and apoptosis. The proteasome inhibitors Bortezomib and Carfilzomib have been approved by the FDA for the treatment of multiple myeloma, proving that the proteasome can be used as a target for anti-tumor drugs. Since the two drugs already on the market are both covalent proteasome inhibitors, the covalent binding mode may lead to serious toxic side effects, and ther...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K5/117C07K5/083C07K1/06A61K38/05A61K38/06A61K38/07A61P35/00A61P37/02A61P29/00
Inventor 肖志艳王克徐凯汤雁波杨颖
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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