Cathepsin inhibitor and its preparation method and application

A cathepsin and composition technology, applied in the preparation of sulfonic acid amide, drug combination, organic chemistry and other directions, can solve the problems of multi-drug resistance, difference in apoptosis sensitivity, affecting the effect of chemotherapy, etc.

Active Publication Date: 2021-04-09
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the apoptosis sensitivity of tumor cells to these drugs is very different, and with the continuous use of such drugs, the multi-drug resistance of tumor cells also greatly affects the effect of chemotherapy

Method used

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  • Cathepsin inhibitor and its preparation method and application
  • Cathepsin inhibitor and its preparation method and application
  • Cathepsin inhibitor and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Embodiment 1: General method for the preparation of (R)-N-benzoylphenylalanine-(S)-2-(4-methoxyl-benzenesulfonamido)-3-phenylpropyl ester

[0113] Step A:

[0114] Dissolve L-phenylalaninol (0.5g, 3.31mmol), triethylamine (0.92ml, 6.62mmol) in dichloromethane (35ml) and cool to 0°C, slowly dissolve 4-methoxy-benzenesulfonyl chloride (0.85g, 3.33mmol) was added dropwise to the reaction liquid, and reacted overnight at room temperature under the protection of nitrogen. Quench the reaction with 5% sodium bicarbonate solution (4ml) and 1M hydrochloric acid solution (7ml), separate the layers, extract the aqueous phase with dichloromethane (2×6ml), combine the organic phases, wash with saturated brine (3× 10ml) was washed, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (chloroform:acetone=300:1) to obtain 1.09g of white solid (1), with a yield of 97%.

[0115] Step B:

[0116] General method for the preparation of (R)-N-tert-butoxyc...

Embodiment 2

[0121] Example 2: Preparation of (R)-N-benzoylphenylalanine-(R)-2-(4-methoxy-benzenesulfonamido)-3-phenylpropyl ester

[0122] The synthetic method is the same as that of Example 1, and the productive rate is 92%. 1 H-NMR (600MHz, CDCl 3 ): δ6.83-7.75 (m, 19H, ArH), 6.75 (d, 1H, J=7.8Hz, 6-NH), 5.19 (d, J=7.8Hz, 1H, 7-NH), 4.95-4.99 (dd, J=13.8, 7.2Hz, 1H, 2-H), 4.16-4.19 (dd, J=10.4, 4.2Hz, 1H, 3a-H), 3.87-3.90 (dd, J=10.4, 4.2Hz, 1H, 3b-H), 3.81(s, 3H, 8-H), 3.62(m, 1H, 4-H), 3.23-3.27(dd, J=13.8, 6.6Hz, 1H, 1a-H), 3.17 -3.21, (dd, J=13.8, 6.6Hz, 1H, 1b-H), 2.67-2.70 (dd, J=13.8, 7.8Hz, 1H, 5a-H), 2.62-2.65 (dd, J=13.8, 6.6Hz, 1H, 5b-H).

Embodiment 3

[0123] Example 3: Preparation of (S)-N-benzoylphenylalanine-(R)-2-(4-methoxy-benzenesulfonamido)-3-phenylpropyl ester

[0124] The synthetic method is the same as that of Example 1, and the productive rate is 92%. 1 H-NMR (600MHz, CDCl 3 ): δ6.86-7.76 (m, 19H, ArH), 6.70 (d, 1H, J=9.0Hz, 6-NH), 4.97-5.01 (dd, J=13.8, 6.6Hz, 1H, 2-H) , 4.80(d, J=8.4Hz, 1H, 7-NH), 4.05-4.06(dd, J=4.8Hz, 2H, 3-H), 3.85(s, 3H, 8-H), 3.60(m, 1H, 4-H), 3.18-3.26 (m, J=2H, 1-H), 2.61-2.63 (dd, 2H, 5-H); 13 C-NMR (150MHz, CDCl 3 ): δ171.4, 167.1, 162.7, 136.1, 135.9, 133.5, 131.9, 131.7, 130.1, 129.2×2, 129.1×2, 129.0×2, 128.8×2, 128.7×2, 128.6×2, 127.2, 127.0, 125.8, 114.2×2, 65.9, 55.5, 53.8, 53.6, 38.2, 37.9.

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Abstract

The invention relates to the field of medicinal chemistry, and relates to a cathepsin inhibitor and a preparation method and application thereof, in particular to a tumor-related cathepsin L and D inhibitor and a preparation thereof. Specifically, the present invention relates to a novel peptoid compound or a pharmaceutically acceptable salt, solvate, pharmaceutical composition, pharmaceutical preparation and a preparation method thereof. And their application in the preparation of antitumor drugs. The structural formula of described compound is as follows: R 1 , R 2 As described in the claims and description.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, and relates to a cathepsin inhibitor and a preparation method and application thereof, in particular to a tumor-related cathepsin L and D inhibitor and a preparation thereof. Specifically, the present invention relates to a novel peptoid compound or a pharmaceutically acceptable salt, solvate, pharmaceutical composition, pharmaceutical preparation and a preparation method thereof. And their application in the preparation of antitumor drugs. Background technique [0002] Malignant tumors are common and frequently occurring diseases that seriously threaten human health and life. Drug therapy plays an important role. At present, the mechanism of action of most cancer therapeutic drugs used clinically is to induce apoptosis. However, the apoptosis sensitivity of tumor cells to these drugs is very different, and with the continuous use of such drugs, the multi-drug resistance of tumor cells also ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C311/29C07C311/17C07C303/40A61K31/18A61P35/00
CPCC07C311/17C07C311/29
Inventor 袁雷马恩龙何文慧
Owner SHENYANG PHARMA UNIVERSITY
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