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1,2,3-triazole aminopeptidase N inhibitor as well as preparation method and application thereof

A technology similar to aminopeptidase and triazole, which is applied in anti-inflammatory agents, pharmaceutical formulations, non-central analgesics, etc., and can solve the problems of high cost of total synthesis, difficult synthesis, unfavorable scientific research and large-scale production

Active Publication Date: 2018-06-29
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is isolated from the culture fluid of Streptomyces olivorecticuli, and its total synthesis is expensive, so the source is limited
Most of the APN inhibitors that have been reported are peptides, which are sensitive to the degradation of enzymes in the body. Due to the existence of various aminopeptidases, carboxypeptidases or dipeptidases in the body, the selectivity is poor, and it is difficult to develop clinical applications. aminopeptidase N inhibitor
In addition, peptide inhibitors are difficult to synthesize because they contain multiple chiral centers, and most of them are derived from natural products. The limited sources are not conducive to in-depth scientific research and large-scale production in the future

Method used

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  • 1,2,3-triazole aminopeptidase N inhibitor as well as preparation method and application thereof
  • 1,2,3-triazole aminopeptidase N inhibitor as well as preparation method and application thereof
  • 1,2,3-triazole aminopeptidase N inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Example 1. (1) Preparation of compounds 8a-8w, 8aa-8ii and 20a-20e, taking compound 8a as an example.

[0103] (S)-2(3-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)ureido)-N-hydroxy-4-methylpentanamide (8a) The preparation method, the steps are as follows:

[0104] 1) Preparation of methyl (prop-2-ynyl-1-ylcarbamoyl)-L-leucine (2)

[0105] L-leucine methyl ester hydrochloride 1 (1.81 g, 10 mmol) was dissolved in a mixed solvent of dichloromethane (40 mL) and saturated sodium bicarbonate (40 mL). Triphosgene (0.98 g, 3.3 mmol) was added in portions. The reaction was carried out at 0°C for 1.5 hours. The organic phase was separated and dried over anhydrous magnesium sulfate for 15 minutes. After filtration, the filtrate was added dropwise to propargylamine (0.55g, 10mmol) and triethylamine (1.21g, 12mmol) in anhydrous dichloromethane (100mL) at 0°C. After dropping, react at 25°C for 12 hours. After concentration, the residue was dissolved in ethyl acetate (100 mL). Wash...

Embodiment 2

[0120] Example 2. The preparation method of compounds 11a-11v, taking compound 11a as an example.

[0121] (S)-N-Hydroxy-4-methyl-2-(3-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)ureido)pentanamide (11a ) preparation method, the steps are as follows:

[0122] 1) Azidobenzene (10a)

[0123] Aniline 9a (0.93g, 10mmol) was dissolved in 3.7% hydrochloric acid, and sodium nitrite (0.74g, 10.7mmol) was added at 0°C. React at 0°C for 0.5 hours, then add sodium azide (0.72 g, 11 mmol). The reaction was continued at 0°C for 0.5 hours. Extracted with ethyl acetate (3×50 mL), the organic phase was dried over anhydrous magnesium sulfate. Filtration and concentration gave a yellow oil. The crude product was directly put into the next reaction without further purification.

[0124] Compounds 10b-10v were prepared in a similar manner to compound 10a.

[0125] 2) (S)-N-Hydroxy-4-methyl-2-(3-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)ureido)pentanamide (11a)

[0126] Compound 3 (0.45g, 2mmol)...

Embodiment 3

[0128] Example 3. The preparation method of compounds 11aa-11ii, taking compound 11aa as an example.

[0129] (S)-2-(4-((3-(1-(hydroxylamine)-4-methyl-1-oxopentan-2-yl)ureido)methyl)-1H-1,2, The preparation method of 3-triazol-1-yl) benzyl acetate (11aa), the steps are as follows:

[0130] 1) (2-nitrophenyl) methanol (13)

[0131] 2-Nitrobenzaldehyde 12 (1.51 g, 10 mmol) was dissolved in methanol (10 mL), and sodium borohydride (0.57 g, 15 mmol) was added in portions at 0°C. React at 0°C for 1 hour. After concentration, the residue was dissolved in ethyl acetate (100 mL). The organic phase was washed with water (3×50 mL), washed with saturated sodium chloride (3×50 mL), and dried overnight over anhydrous magnesium sulfate. Filtration and concentration gave a yellow solid (1.45g). The crude product was directly put into the next reaction without further purification.

[0132] 2) (2-aminophenyl) methanol (14)

[0133] Compound 13 (1.53 g, 10 mmol) was added to a solution ...

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Abstract

The invention discloses a 1,2,3-triazole aminopeptidase N inhibitor as well as a preparation method and application thereof. A compound of the invention has a structure represented by a formula (I) or(II). The invention also provides a preparation method of a 1,2,3-triazole compound and application in preparation of a medicament for preventing or treating a disease associated with abnormal aminopeptidase activity. The formulas (I) and (II) are shown in the specification.

Description

technical field [0001] The invention relates to a 1,2,3-triazole aminopeptidase N inhibitor, a preparation method and application thereof, and belongs to the technical field of organic compound synthesis and medical application. Background technique [0002] Aminopeptidase N (APN, CD13) is a zinc ion-dependent metalloprotease that participates in the degradation of N-terminal amino acids of substrates and exists in the cell membrane in the form of homodimers. , invasion and metastasis, apoptosis and tumor angiogenesis play an important role. (1) Aminopeptidase N is highly expressed on the surface of tumor cells. The enzyme can degrade the extracellular matrix, thereby promoting the invasion and metastasis of tumor cells. Tumor metastasis is an important reason why tumors are difficult to cure. The extracellular matrix plays a very important role in maintaining the stability of cell junctions and intercellular signaling. (2) Aminopeptidase N can stimulate vascular endothe...

Claims

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Application Information

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IPC IPC(8): C07D249/04C07D249/06A61K31/4192A61P35/00A61P29/00A61P33/06A61P17/02A61P1/02A61P37/02A61P25/00
CPCC07D249/04C07D249/06Y02A50/30
Inventor 张颖杰徐文方曹江营
Owner SHANDONG UNIV
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