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Cyclin imide peptidyl metalloprotease inhibitor and its application

A metalloprotease and acetamide-based technology, applied in dipeptides, medical preparations containing active ingredients, drug combinations, etc., can solve problems such as no consideration of selectivity, limited sources, and poor member selectivity

Inactive Publication Date: 2009-11-18
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

2) APN is abundantly expressed on the surface of granulocytes and lymphocytes, and is also involved in T lymphocyte-dependent inflammatory responses; it can also be expressed on the surface of antigen-presenting cells to degrade immune active substances (such as interleukin-8); it is involved in antigen processing and The major histocompatibility complex type II (MHC-II) adhesion epitope on the cell surface depends on the recognition of antigens by T cells, which reduces the recognition ability of T cells and at the same time weakens the ability of macrophages and NK cells to tumor The ability to identify and kill cells reduces the body's immunity
[0009] Since the 1990s, many MMPs inhibitors have been developed, most of which are peptides or peptide analogs, which are more sensitive to enzymatic degradation. In addition, because most of them have long-chain structures and contain a large number of rotatable single bonds, they are not suitable for MMPs. Members of the same family have poor selectivity, which is why most MMPs inhibitors are shot down in the clinical stage
In addition, most of the inhibitors against APN are natural products. The only drug on the market, Ubenimex, has a dipeptide-like structure containing β-amino acids. It is currently used as an immune enhancer for the treatment of leukemia. Isolated from the culture fluid of Streptomycesolivorecticuli, the source is limited
The metalloprotease inhibitors reported in the current literature do not take into account the selectivity of the two (endopeptidase and exopeptidase), so there is no in-depth discussion on the mechanism of action

Method used

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  • Cyclin imide peptidyl metalloprotease inhibitor and its application
  • Cyclin imide peptidyl metalloprotease inhibitor and its application
  • Cyclin imide peptidyl metalloprotease inhibitor and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Example 1. Preparation of (S)-2-(3,4,5-trimethoxybenzamido)glutaric acid (4)

[0090] 1) 3,4,5-Trimethoxybenzoic acid (2). Dissolve NaOH (80g, 2mol) in 500ml distilled water, cool to room temperature, add 3,4,5-trihydroxybenzoic acid (gallic acid, 50g, 0.294mol), immediately stopper, stir until dissolved. Control the internal temperature below 20°C, add (CH 3 ) 2 SO 4 (89g, 67ml, 0.71mol), at this time the temperature can rise to 30-45°C, open the cork from time to time to deflate. After 20min, add the second batch of equal amount of (CH 3 ) 2 SO 4 At this time, the temperature can rise to 40-45°C, stir for 10 minutes, heat up and boil for 2 hours. Then add 50g of 40% NaOH solution and boil for 2h to saponify the ester that may be generated. The reaction solution was cooled to room temperature, acidified with dilute hydrochloric acid, filtered with suction, and the filter cake was washed with cold water to obtain 48 g of crude product.

[0091] Crude refinement...

Embodiment 2

[0094] Example 2. Preparation of (S)-2-(2,6-dioxo-3-(3,4,5-trimethoxybenzamido)piperidin-1-yl)acetic acid (6)

[0095] 1) (S)-N-(2,6-Dioxy-tetrahydro-2H-pyran-3-yl)-3,4,5-trimethoxybenzamide (5). 3,4,5-trimethoxybenzoylglutamic acid (10g, 2.9mmol), add 80ml of acetic anhydride, and keep warm in an oil bath at 55-60°C for 5h. Remove the insoluble matter by filtration while hot, add an appropriate amount of anhydrous ether, cool, and precipitate a white solid. 5.2 g was weighed by filtration, yield 55%, mp 150-152°C. IR (KBr, cm-1): 3310.0, 2945.1, 1777.0, 1640.7, 1504.2, 1239.6, 1129.6; ESI-MS: m / z 323.8.

[0096] 2) (S)-2-(2,6-Dioxy-3-(3,4,5-trimethoxybenzamido)piperidin-1-yl)acetic acid (6). Compound 5 (5.0 g) was dissolved in 50 ml of DMF, 1.0 g of glycine was ground and added to DMF, and heated at 110° C. for 5 hours. The mixture was cooled to room temperature, poured into an equal volume of ice water with a pH of 2, and left overnight, a large amount of white crystals ...

Embodiment 3

[0097] Example 3. (S)-methyl-2-(2-(2,6-dioxo-3-(3,4,5-trimethoxybenzamido)piperidin-1-yl)acetamide base) Acetate (7a).

[0098] Compound 6 (1.90g, 5mmol) and HoBt (0.81g, 6mmol) were dissolved in 20ml of dichloromethane and 2ml of dimethyl sulfoxide, cooled to 0°C in an ice bath, and slowly added dropwise with EDCI (1.44g, 7.5mmol). Chloromethane solution was added dropwise in about 1 hour, then removed from the ice bath and stirred for 2 hours. Glycine methyl ester hydrochloride (0.75 g, 6 mmol) was added in batches in an ice bath, and the pH value was adjusted to 7 with triethylamine. After the ice cubes melted automatically, the stirring was continued overnight. The reaction solution was successively washed with 1N hydrochloric acid, 1% sodium carbonate, saturated brine, dried over sodium sulfate, and purified by column chromatography to obtain the final product with a yield of 79%. mp98.7-100.6℃. 1 HNMR (400MHz, DMSO-d6, ppm): δ9.04(t, 1H), 8.88(d, 1H), 7.17(s, 2H), 4.5...

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Abstract

Cyclic imide peptide metalloprotease inhibitors and applications thereof. The invention provides a class of potent peptide-like metalloprotease inhibitors, which exhibit remarkable selectivity between endopeptidase and exopeptidase, and can effectively treat diseases with abnormal expression of metalloprotease activity. Specifically, the present invention relates to a peptoid compound having a structure of general formula (I), and various optical isomers, pharmaceutically acceptable salts, solvates and prodrugs thereof. The present invention also relates to a pharmaceutical composition containing the structural peptoid compound of formula (I) and its pharmaceutical application.

Description

technical field [0001] The present invention relates to a preparation method, an activity test, a composition containing the peptidoid compound and the application of a class of peptidoid compound selectively inhibiting metalloprotease with a cyclic imide peptidoid skeleton. Background technique [0002] 1. Matrix metalloproteinases (MMPs) [0003] MMPs are a class of endopeptidases dependent on calcium ions and zinc ions. The activity of MMPs is strictly controlled by the expression level of genes and the secretion level of zymogen activators / inhibitors. MMPs play an important role in the degradation of extracellular matrix and tissue reconstruction. In many pathological processes, such as arthritis, tissue ulceration, growth and metastasis of malignant tumors, MMPs also play an important role. [0004] At present, 28 members of the MMPs family have been found in mammals (Szabo, K.A. et al. Clinical and Applied Immunology Reviews. 2004, 4, 295), which are divided into dif...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/88C07K5/06A61K31/4412A61P35/00
Inventor 徐文方李乾斌
Owner SHANDONG UNIV
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