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Kallikrein 7 small-molecule inhibitor as well as preparation method and application thereof

A technology of small molecule inhibitors and kallikrein, which is applied in skin diseases, organic chemistry, drug combination, etc., can solve the problems of limited effect, fast degradation speed, and inability to penetrate the stratum corneum of the skin, so as to achieve convenient operation and absorption Fast, inhibits the effect of KLK7

Inactive Publication Date: 2016-01-06
HENGYANG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although LEKTI is a natural inhibitor of KLK7 in the epidermis, as an external drug for the treatment of AD, it cannot penetrate the stratum corneum of the skin. At the same time, due to the characteristics of its macromolecular protein, it will degrade too quickly, so LEKTI is used as an external drug. very limited
And, so far, there is no effective small molecule inhibitor of KLK7 used in clinical

Method used

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  • Kallikrein 7 small-molecule inhibitor as well as preparation method and application thereof
  • Kallikrein 7 small-molecule inhibitor as well as preparation method and application thereof
  • Kallikrein 7 small-molecule inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Preparation of Kallikrein 7 Small Molecule Inhibitors

[0042] 1.0mol compound (Ⅱ) was dissolved in 2.0mol concentrated H 2 SO 4 In, add dropwise 1.0mol concentrated H 2 SO 4 with 1.0mol concentrated HNO 3 The formed mixed acid was controlled at a temperature below 30° C. and reacted for 4 hours to obtain compound (Ⅲ), poured into ice water, filtered to obtain crude compound (Ⅲ), and separated by column to obtain compound (Ⅲ).

[0043] Add 25 mol of water, 3.0 mol of iron powder, 0.3 mol of HCl (100% hydrogen chloride, 37% concentration) in the reaction bottle, control the temperature at 90° C., add compound (Ⅲ) in batches, react for 3 hours, neutralize with sodium carbonate, pass Compound (Ⅳ) was obtained by column separation.

[0044]Add compound (Ⅳ), ether, triethylamine to the reaction flask, then add succinoyl chloride dropwise, react at room temperature for 2 hours, compound (Ⅳ): ether: triethylamine: succinoyl chloride = 1:5:2.5:1 (molar ratio), ...

Embodiment 2

[0051] Example 2: Preparation of Kallikrein 7 Small Molecule Inhibitors

[0052] 1.0mol compound (Ⅱ) was dissolved in 2.0mol concentrated H 2 SO 4 In, add dropwise 1.0mol concentrated H 2 SO 4 with 1.0mol concentrated HNO 3 The formed mixed acid was controlled at a temperature below 30° C., and reacted for 6 hours to obtain compound (Ⅲ), which was poured into ice water, filtered to obtain crude compound (Ⅲ), and separated by column to obtain compound (Ⅲ).

[0053] Add 20 mol of water, 2.0 mol of iron powder, 0.1 mol of HCl (100% hydrogen chloride, 37% concentration) in the reaction bottle, control the temperature at 90°C, add compound (Ⅲ) in batches, react for 2 hours, neutralize with sodium carbonate, pass Compound (Ⅳ) was obtained by column separation.

[0054] Add compound (Ⅳ), diethyl ether and triethylamine to the reaction flask, then add succinoyl chloride dropwise, and react at room temperature for 2 hours, compound (Ⅳ): ether: triethylamine: succinoyl chloride=0.5...

Embodiment 3

[0060] Example 3: Preparation of Kallikrein 7 Small Molecule Inhibitors

[0061] 1.0mol compound (Ⅱ) was dissolved in 2.0mol concentrated H 2 SO 4 In, add dropwise 1.0mol concentrated H 2 SO 4 with 1.0mol concentrated HNO 3 The formed mixed acid was controlled at a temperature below 30° C., and reacted for 6 hours to obtain compound (Ⅲ), which was poured into ice water, filtered to obtain crude compound (Ⅲ), and separated by column to obtain compound (Ⅲ).

[0062] Add 30 mol of water, 5 mol of iron powder, 0.5 mol of HCl (100% hydrogen chloride, 37% concentration) into the reaction bottle, control the temperature at 90°C, add compound (Ⅲ) in batches, react for 3 hours, neutralize with sodium carbonate, and pass through the column Compound (IV) was isolated.

[0063] Add compound (Ⅳ), ether, triethylamine to the reaction flask, then add succinoyl chloride dropwise, react at room temperature for 2 hours, compound (Ⅳ): ether: triethylamine: succinoyl chloride = 2:6:3.5:2 (m...

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Abstract

The invention discloses a kallikrein 7 small-molecule inhibitor. The structure of the kallikrein 7 small-molecule inhibitor is expressed by a formula (I). The invention further provides a preparation method of the kallikrein 7 small-molecule inhibitor. The kallikrein 7 small-molecule inhibitor can be used for inhibiting the activity of kallikrein 7 and preparing a medicine for treating atopic dermatitis, and can also be used as an effective component of a pharmaceutical composition for treating the atopic dermatitis; the pharmaceutical composition can be used as an external ointment or external spray preparation. The inhibiter is capable of effectively inhibiting the kallikrein 7 as the small-molecule inhibitor, and has the prospect of preparing the medicine for treating the atopic dermatitis.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a small-molecule inhibitor of kallikrein 7 and its preparation method and application. Background technique [0002] Atopic dermatitis (AD) is a widespread chronic inflammatory skin disease characterized by dry, scaly skin, inflammation, and increased skin permeability. The skin of AD patients is sensitive to the common in the environment but not harmful to normal people. Factors can also be sensitive to surface infection. The incidence of atopic dermatitis in industrialized countries has increased two to threefold over the past 30 years, with an estimated prevalence of 15–30% in children and 10% in adults. up 2-10%. Due to the complexity of the pathogenesis, the pathogenesis of AD is not well understood, but skin barrier dysfunction has been confirmed to be one of the key factors in the development of AD. [0003] The stability of the skin barrier depends on the balance bet...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/5025A61P17/00
CPCC07D487/04
Inventor 王芳宇谭潇王德平严加林何丽芳周冬升李玉林
Owner HENGYANG NORMAL UNIV