Cathepsin inhibitor as well as preparation method and application thereof

A C1-C6, alkyl technology, applied in cathepsin inhibitors and their preparation, the application field in the preparation of antitumor drugs, can solve the problems of multi-drug resistance, difference in apoptosis sensitivity, affecting the effect of chemotherapy, etc.

Inactive Publication Date: 2020-02-21
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 as well as preparation method and application thereof
  • Cathepsin inhibitor as well as preparation method and application thereof
  • Cathepsin inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0189] Example 1: General method for the preparation of (R)-N-substituted phenylsulfonyl phenylalanine-(S or R)-2-substituted benzamido-3-phenylpropyl ester (1)

[0190] Step A: General method for the preparation of (R or S)-N-tert-butoxycarbonylphenylalanine-(S or R)-2-substituted benzamido-3-phenylpropyl ester

[0191] N-tert-butoxycarbonyl (Boc)-D(or L)-phenylalanine (0.2g, 0.75mmol) was dissolved in dry dichloromethane (10ml) and (N,N')-carbonyldiimidazole was added (0.15g, 0.93mmol), stirred at room temperature for 30min. Then various N-(substituted benzoylated)-phenylalaninols (0.28 g, 0.75 mmol) diluted with dichloromethane (10 ml) were added into the reaction system, and finally reacted overnight at room temperature. Silica gel column chromatography (chloroform:acetone=500:1) gave a white solid with a yield of 64-85%.

[0192] Step B:

[0193] General method for the preparation of (R or S)-N-substituted phenylsulfonyl phenylalanine-(S or R)-2-substituted benzamido-3...

Embodiment 2

[0195] Example 2: Preparation of (R)-N-(4-bromobenzenesulfonyl)-phenylalanine-(S)-2-benzamido-3-phenylpropyl ester

[0196] The synthetic method is the same as that of Example 1, and the productive rate is 89%. 1 H-NMR (600MHz, CDCl 3 ): δ7.00-7.75(m, 19H, ArH), 6.53(d, 1H, J=7.8Hz, 6-NH), 5.18(d, J=9.0Hz, 1H, 7-NH), 4.61(m ,1H,4-H),4.34-4.36(d,J=9.6Hz,1H,3a-H),4.11(d,J=5.4Hz,1H,2-H),4.03(dd,J=7.2Hz ,1H,3b-H),3.06-3.10(dd,J=13.8,5.4Hz,1H,1a-H),2.97-3.00(dd,J=13.8,6.6Hz,1H,5a-H),2.87- 2.93 (dd, J=13.8, 6.6Hz, 2H, 1b-H, 5b-H); 13 C-NMR (150MHz, CDCl 3 ):δ170.6,167.1,138.2,136.9,134.8,134.0,132.2×2,131.6,129.2×2,129.0×2,128.7×2,128.7×2,128.4×2,128.4×2,127.8,127.3,127.0×2,126.8,66.2,57.3,49.8,38.7,37.2.

Embodiment 3

[0197] Example 3: Preparation of (R)-N-(4-bromobenzenesulfonyl)-phenylalanine-(R)-2-benzamido-3-phenylpropyl ester

[0198] The synthetic method is the same as in Example 1, and the productive rate is 85%. 1 H-NMR (600MHz, CDCl 3 ):δ7.02-7.73(m,19H,ArH),6.45(d,1H,J=8.4Hz,6-NH),5.17(d,J=9.6Hz,1H,7-NH),4.59(m ,1H,4-H),4.25-4.28(dd,J=11.4,3.0Hz,1H,3a-H),4.17-4.21(dd,J=14.4,8.4Hz,1H,2-H),4.12- 4.15(dd, J=11.4, 4.8Hz, 1H, 3b-H), 3.08-3.11(dd, J=13.8, 5.4Hz, 1H, 1a-H), 2.98-2.95(dd, J=13.8, 6.6Hz ,1H,5a-H),2.92-2.88(dd,J=13.8,6.6Hz,1H,1b-H),2.83-2.87(dd,J=13.8,6.6Hz,1H,5b-H).

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Abstract

The invention relates to the field of medicine chemicals, relates to a cathepsin inhibitor as well as a preparation method and application thereof, and in particular relates to a novel peptoid compound or a pharmaceutically acceptable solvent compound, a medicine composition and a medicine preparation thereof, and a preparation method of the novel peptoid compound. The invention further relates toapplication of the compound or the pharmaceutically acceptable solvent compound, the medicine composition and the medicine preparation thereof. The compound and isomers thereof are shown in a formula(I) shown in the description, in the formula, R1 and R2 are shown in the description and the claims.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, relates to a cathepsin inhibitor and its preparation method and application, in particular to a novel peptidoid compound or a pharmaceutically acceptable solvate thereof, a pharmaceutical composition, a pharmaceutical preparation and a preparation method thereof. It also relates to the application of the compound or its pharmaceutically acceptable solvate, pharmaceutical composition and pharmaceutical preparation in the preparation of antitumor drugs. Background technique [0002] Malignant tumors are common and frequently occurring diseases that seriously threaten human health and life (Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2017. CA Cancer J. Clin., 2017, 67(1): 7-30). Drug therapy occupies an important position. At present, the mechanism of action of most cancer therapeutic drugs used clinically is to induce tumor cell apoptosis. However, the apoptosis sensitivity of tumor ce...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/19C07C311/29C07C311/42C07C303/36C07C269/06C07C271/22A61K31/216A61P35/00
CPCA61P35/00C07C271/22C07C311/19C07C311/29C07C311/42
Inventor 袁雷马恩龙
Owner SHENYANG PHARMA UNIVERSITY
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