CN109172568A - 一种吡咯衍生物的新用途 - Google Patents

一种吡咯衍生物的新用途 Download PDF

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CN109172568A
CN109172568A CN201811103498.9A CN201811103498A CN109172568A CN 109172568 A CN109172568 A CN 109172568A CN 201811103498 A CN201811103498 A CN 201811103498A CN 109172568 A CN109172568 A CN 109172568A
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azole derivatives
new application
formula
hydrogen
application
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徐学涛
吕卉
黄丹颖
张焜
李冬利
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International Healthcare Innovation Institute (jiangmen)
Wuyi University
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International Healthcare Innovation Institute (jiangmen)
Wuyi University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

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Abstract

本发明公开了一种吡咯衍生物的新用途，所述吡咯衍生物结构通式如式(Ⅰ)所示：

Description

一种吡咯衍生物的新用途
技术领域
本发明涉及医药领域，具体涉及一种吡咯衍生物的新用途。
技术背景
酪氨酸酶即多酚氧化酶，是二价铜离子与酶蛋白相结合的一种金属酶，广泛存在于动物、植物及真菌中。它也是参与黑色素合成的关键酶之一，控制着黑色素的形成过程，其活性程度对色素的沉积起主要作用。目前市场上广泛使用的许多美白祛斑产品都是通过抑制酪氨酸酶途径发挥其作用。包括龙胆酸衍生物、抗坏血酸衍生物、熊果苷和氢醌等，但其中许多化合物已经被证实对皮肤细胞有致变等毒性作用。因此，继续寻找和发现新型、高效且安全的美白祛斑活性化合物仍是当前研究的热点。
发明内容
本发明的目的在于提供一种吡咯衍生物在酪氨酸酶抑制剂和治疗色素沉着、色斑、白癜风的药物中的应用。
所述吡咯衍生物的结构通式如下：
其中：
(1)R1，R2可为氢、氟、氯、溴、甲氧基、甲基、乙基、异丙基、硝基、三氟甲基；
(2)R3可为氢、酰胺基。
具体实施方式
为了更好的说明本发明的目的、技术方案和优点，下面将结合具体实施例对本发明进行说明。
实施例1
本实施例研究本发明所述吡咯衍生物在体外抑制酪氨酸酶的作用。
将本发明的化合物全部溶解在二甲基亚峰中，配置成浓度为2mmol/L的母液，待用。在96孔板中，将10μL待测化合物、10μL酪氨酸酶(浓度为666.6U/mL)与130μL磷酸盐缓冲溶液(浓度为50mmol/L)混合均匀后加入50μL L-DOPA(浓度为1mmol/L)，混合均匀后在475nm波长下测定1分钟吸光度的变化。以二甲基亚峰作为空白对照组。抑制活性＝[吸光度(空白)-吸光度(化合物)]/吸光度(空白)×100％。吡咯衍生物在终浓度100μmol/L时抑制酪氨酸酶活性如表1所示：
表1吡咯衍生物在终浓度100μmol/L时抑制酪氨酸酶活性
化合物编号 R<sub>1</sub> R<sub>2</sub> R<sub>3</sub> 抑制率(％)
1 甲氧基 氢 式(a) 15
2 氢 氯 式(a) 18
3 氟 氢 式(a) 20
4 溴 氢 式(a) 60
5 氢 甲基 式(a) 14
6 氢 溴 式(a) 12
7 三氟甲基 氢 式(a) 20
8 溴 氢 式(b) 18
9 甲氧基 氢 式(b) 60
10 氢 氢 式(b) 15
11 氢 三氟甲基 式(b) 20
12 氢 氯 式(b) 30
13 氟 氢 式(b) 18
14 氢 甲基 式(b) 17
15 氢 溴 式(b) 15
实施例2
本实施例研究本发明化合物4体外抑制酪氨酸酶的半数抑制浓度。
配置不同浓度的化合物4的母液，包括：10mmol/L、8mmol/L、6mmol/L、4mmol/L、2mmol/L、1mmol/L、0.8mmol/L、0.6mmol/L、0.4mmol/L、0.2mmol/L。在96孔板中，将10μL待测化合物、10μL酪氨酸酶(浓度为666.6U/mL)与130μL磷酸盐缓冲溶液(浓度为50mmol/L)混合均匀后加入50μL L-DOPA(浓度为1mmol/L)，混合均匀后在475nm波长下测定1分钟吸光度的变化。以二甲基亚峰作为空白对照组。抑制活性＝[吸光度(空白)-吸光度(化合物)]/吸光度(空白)×100％。通过不同浓度化合物的抑制率，可求得化合物的半数抑制浓度，本实施例化合物4体外抑制酪氨酸酶的半数抑制浓度为80.4μmol/L。

Claims (3)

1.一种吡咯衍生物的新用途，其特征在于，所述吡咯衍生物具有如下结构通式：
其中：
(1)R1，R2可为氢、氟、氯、溴、甲氧基、甲基或三氟甲基；
(2)R3为式a或b：
2.根据权利要求1所述一种吡咯衍生物的新用途，其特征在于，所述新用途为在制备酪氨酸酶抑制剂中的应用。
3.根据权利要求1所述一种吡咯衍生物的新用途，其特征在于，所述新用途为在制备治疗色素沉着、色斑、白癜风的药物中的应用。
CN201811103498.9A 2018-09-20 2018-09-20 一种吡咯衍生物的新用途 Pending CN109172568A (zh)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101795733A (zh) * 2007-08-13 2010-08-04 默克专利股份有限公司 酪氨酸酶抑制剂

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101795733A (zh) * 2007-08-13 2010-08-04 默克专利股份有限公司 酪氨酸酶抑制剂

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
胡泳华等: "酪氨酸酶抑制剂的应用研究进展", 《厦门大学学报（自然科学版）》 *

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