Alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and application thereof

A technology of amino and natural amino acids, which is applied in the field of metalloproteinase inhibitors, can solve the problems of decreased immunity, large number of rotatable single bonds, and reduced T cell recognition ability, etc., to improve compatibility and significantly inhibit enzyme activity in vitro Effect

Inactive Publication Date: 2009-09-23
SHANDONG UNIV
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  • Abstract
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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 matrix metalloproteinase (MMPs) inhibitors have been developed, most of which are peptides or peptide analogs, which are sensitive to enzyme degradation. In addition, because most of them have long-chain structures, the number of rotatable single bonds contained More, so the selectivity to members of the same family is not good, which is why most matrix metalloproteinase (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 medium of Streptomyces olivorecticuli, 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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  • Alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and application thereof
  • Alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and application thereof
  • Alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Example 1. Ethyl 2-((S)-3-((S)-2-amino-3-phenylpropionamido)-2,6-dioxopiperidin-1-yl)acetate salt Preparation of acid salt (6f)

[0117]

[0118] (S)-tert-butyl 2,6-dioxopiperidin-3-ylcarbonamide (2)

[0119] Boc-L-glutamine (41.6g, 0.17mol) and N-hydroxysuccinimide (NIISu, 19.5g, 0.17mol) were dissolved in 200ml THF, and 100ml containing DCC (35.1 g, 0.17mol) in THF. After about 1 hour of dripping, remove the ice and stir in the bathroom for 3 hours, then reflux for 10 hours. The reaction solution was cooled to room temperature, and the solvent was recovered by rotary evaporation. The residue was added to 50 ml of ethyl acetate and concentrated once more. After the final residue was added with 200ml of ethyl acetate, it was frozen in the refrigerator overnight. Filter with 4.0 grams of diatomaceous earth, wash the filtrate with water (50ml*1) and saturated brine (50ml*1), NaSO 4 Dry. Filter and concentrate to dryness. Refined with ethyl acetate-diethyl ether ...

Embodiment 2

[0129] Example 2. 2-((S)-3-((S)-2-Amino-4-methylpentanamido)-2,6-dioxopiperidin-1-yl)acetic acid hydrochloride (11d) preparation of

[0130]

[0131] (S)-Benzyl-2-(3-(tert-butoxycarbonylamido)-2,6-dioxopiperidin-1-yl)acetate (7)

[0132] Compound 2 (18.3g, 0.086mol), K 2 CO 3 (14.2g, 1.2e.q), tetrabutylammonium iodide (TBAI, 3.1g, 0.1e.q.) was swirled in 300ml of anhydrous acetone. Benzyl bromoacetate (30.0 g, 1.5 e.q.) was added slowly at room temperature. The reaction solution was refluxed for 7 hours and cooled to room temperature. Filter and concentrate to obtain a yellow oil. Add 200ml of ethyl acetate, and the organic phase is respectively washed with 0.5% Na 2 CO 3 (20ml*2), 5% citric acid (20ml*2), washed with saturated brine until neutral, dried the organic phase with anhydrous sodium sulfate, filtered, concentrated and recrystallized with ethyl acetate-ether to obtain 20.8g of 7 white crystals , yield 67%. mp 78.0-81.0℃; ESI-MS m / z[M+1] + : 377.6; 1H-NMR...

Embodiment 3

[0140] Example 3. Tert-butyl (S)-1-((S)-1-(2-(hydroxylamino)-2-oxoethyl)-2,6-dioxopiperidine-3-amino)- Preparation of 4-methyl-1-oxopentane-2-carboxylate (13d)

[0141]

[0142] Dissolve 0.2g (3.0mmol) of hydroxylamine hydrochloride in 1.5ml of anhydrous methanol, slowly add 0.5ml (2e.q) of triethylamine to free the amino groups, accurately measure the supernatant, and set aside.

[0143] Dissolve 2.0mmol of carboxylic acid derivative 10d in 20ml of anhydrous THF, control the solution temperature not higher than -20°C, slowly add 4.0mmol (0.57ml) triethylamine, and slowly add 2.02mmol (0.28ml) of chloroformic acid iso Butyl ester (ISC), white turbidity indicates that the reaction to prepare mixed anhydride has occurred. The reaction solution was stirred at -20°C for 15 minutes, and the methanol solution containing hydroxylamine was slowly added dropwise to the mixed anhydride reaction solution, and the drop was completed in about 20 minutes. Continue to keep warm at -20°C...

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Abstract

The invention relates to an alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and an application thereof. The invention provides a powerful peptoid metalloprotease inhibitor which embodies outstanding selectivity between endopeptidases and exopeptidases so as to effectively treat diseases expressed by abnormal metalloprotease activity. Specifically, the invention relates to a peptoid compound with a structure of a general formula (I) and salt thereof acceptable on pharmacy. The invention also relates to a medical composition of the peptoid compound with the structure of the formula (I) and the pharmacy application thereof.

Description

technical field [0001] The invention relates to a class of metalloprotease inhibitors with an α-aminoacylcycloimide peptide skeleton, a preparation method and application thereof, and belongs to the field of chemical technology. Background technique [0002] 1. Matrix metalloproteinases (MMPs) [0003] Matrix metalloproteinases (MMPs) are a class of endopeptidases that depend on calcium ions and zinc ions. The activity of matrix metalloproteinases (MMPs) is strictly controlled by the level of gene expression and the secretion level of zymogen activators / inhibitors. Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix and tissue reconstruction. Matrix metalloproteinases (MMPs) also play an important role in many pathological processes, such as arthritis, tissue ulceration, growth and metastasis of malignant tumors. [0004] At present, 28 members of the matrix metalloproteinase (MMPs) family have been found in mammals (Szabo, K....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K5/083C07K5/087C07K5/09C07K5/103C07K5/107C07K5/11C07D211/88C07D207/416C07K1/06A61K38/05A61K38/06A61K38/07A61P29/00A61P35/00A61P25/28A61P1/04A61P17/02A61P1/02A61P17/00A61P35/02
CPCY02P20/55
Inventor 徐文方李乾斌王学建方浩
Owner SHANDONG UNIV
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