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Cathepsin inhibitor, preparation method and applications thereof

A solvate and compound technology, applied in the field of medicinal chemistry, can solve problems such as multi-drug resistance, differences in apoptosis sensitivity, and effects of chemotherapy effects

Active Publication Date: 2018-07-06
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, preparation method and applications thereof
  • Cathepsin inhibitor, preparation method and applications thereof
  • Cathepsin inhibitor, preparation method and applications thereof

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, particularly to a cathepsin inhibitor, a preparation method and applications thereof, more particularly to a tumor-associated cathepsin L inhibitor and a tumor-associated cathepsin D inhibitor, and a preparation method of the tumor-associated cathepsin L inhibitor and the tumor-associated cathepsin D inhibitor. Specifically the present invention further relates to a novel peptoid compound or a pharmaceutically acceptable salt thereof, a solvate, a pharmaceutical composition and a pharmaceutical preparation, a preparation method of thecompound, and applications of the peptoid compound or the pharmaceutically acceptable salt thereof, the solvate, the pharmaceutical composition and the pharmaceutical preparation in preparation of antitumor drugs, wherein the structure formula of the compound is defined in the specification, and R1, R2 are defined in the claims and the specification. The formula (I) is defined in the specification.

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 Applications(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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