阅读说明：本技术 二氢青蒿素的硫醚、亚砜与砜衍生物及其应用 (Thioether, sulfoxide and sulfone derivatives of dihydroartemisinin and application thereof ) 是由 杨大成 张书虹 范莉 刘建 唐雪梅 孟然然 于 2019-09-26 设计创作，主要内容包括：本发明公开了式I所示的二氢青蒿素的硫醚、亚砜与砜衍生物,式中,n为1或2,m为0时,Y为<Image he="125" wi="272" file="DDA0002217120010000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>或<Image he="160" wi="296" file="DDA0002217120010000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>n＝2,m＝0时,Y为<Image he="149" wi="210" file="DDA0002217120010000013.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>n为1或2,m为1或2时,Y为<Image he="157" wi="597" file="DDA0002217120010000014.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>或<Image he="150" wi="213" file="DDA0002217120010000015.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>R<Sub>1</Sub>、R<Sub>2</Sub>和R<Sub>3</Sub>各自独立地为H、卤素、C1-C6烷基、C1-C6烷氧基、羟基、氨基、C1-C6烷胺基或C1-C6烷酰胺基；还公开了所述二氢青蒿素的硫醚、亚砜与砜衍生物在制备抗疟药物、抗利什曼原虫药物、抗血管生成药物、抗肿瘤药物、降血脂药物或/和Wnt信号通路激动剂中的应用。<Image he="293" wi="606" file="DDA0002217120010000016.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses thioether, sulfoxide and sulfone derivatives of dihydroartemisinin shown as a formula I, wherein n is 1 or 2, when m is 0, Y is Or When n is 2, m is 0, Y is n is 1 or 2, when m is 1 or 2, Y is Or R 1 、R 2 And R 3 Each independently is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, amino, C1-C6 alkylamino, or C1-C6 alkylamido; also discloses the application of the thioether, sulfoxide and sulfone derivatives of the dihydroartemisinin in the preparation of antimalarial drugs, anti-leishmanial drugs, anti-angiogenesis drugs, anti-tumor drugs, hypolipidemic drugs or/and Wnt signal pathway agonists.)

1. Thioether, sulfoxide and sulfone derivatives of dihydroartemisinin shown as formula I or racemate, stereoisomer, tautomer, oxynitride and pharmaceutically acceptable salt thereof:

in the formula I, n is 1 or 2, when m is 0, Y is

R₁、R₂And R₃Each independently is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, amino, C1-C6 alkylamino, or C1-C6 alkylamido.

2. Thioether, sulfoxide and sulfone derivatives of dihydroartemisinin, or its racemate, stereoisomer, tautomer, nitroxide, pharmaceutically acceptable salt, as claimed in claim 1, characterized in that: r₁、R₂And R₃Each independently is H, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, or C1-C3 alkylamido.

3. Thioether, sulfoxide and sulfone derivatives of dihydroartemisinin, or its racemate, stereoisomer, tautomer, nitroxide, pharmaceutically acceptable salt, as claimed in claim 2, characterized in that: r₁、R₂And R₃Independently H, methoxy, amino or acetylamino.

4. Thioether, sulfoxide and sulfone derivatives of dihydroartemisinin, or its racemate, stereoisomer, tautomer, nitroxide, pharmaceutically acceptable salt, as claimed in claim 3, characterized in that: n is 1 or 2, when m is 0, Y is

5. Use of the thioether, sulfoxide and sulfone derivatives of dihydroartemisinin, or the racemates, stereoisomers, tautomers, nitroxides, pharmaceutically acceptable salts thereof, according to claim 1, for the preparation of antimalarial drugs.

6. Use of thioether, sulfoxide and sulfone derivatives of dihydroartemisinin, or its racemate, stereoisomer, tautomer, nitroxide, pharmaceutically acceptable salt, as claimed in claim 1, for the preparation of a medicament against leishmania.

7. Use of the thioether, sulfoxide and sulfone derivatives of dihydroartemisinin, or the racemates, stereoisomers, tautomers, nitroxides, pharmaceutically acceptable salts thereof, according to claim 1, for the preparation of a medicament for anti-angiogenesis.

8. The use of the thioether, sulfoxide and sulfone derivatives of dihydroartemisinin, or the racemates, stereoisomers, tautomers, nitroxides, pharmaceutically acceptable salts thereof, as claimed in claim 1, in the preparation of an antitumor medicament.

9. Use of the thioether, sulfoxide and sulfone derivatives of dihydroartemisinin, or the racemates, stereoisomers, tautomers, nitroxides, pharmaceutically acceptable salts thereof, as claimed in claim 1, for the preparation of a hypolipidemic agent.

10. Use of thioether, sulfoxide and sulfone derivatives of dihydroartemisinin, or its racemate, stereoisomer, tautomer, nitroxide, pharmaceutically acceptable salt, as claimed in claim 1, for the preparation of Wnt signaling pathway agonists.

Technical Field

The invention belongs to the technical field of drug synthesis, and relates to thioether, sulfoxide and sulfone derivatives of dihydroartemisinin and pharmaceutical application thereof.

Background

Dihydroartemisinin (DHA) is an artemisinin derivative, and has high-efficiency and low-toxicity antimalarial activity. In recent years, the studies show that the dihydroartemisinin and the derivatives thereof also have various biological activities of resisting tumors, inflammation, tissue fibrosis and the like.

The research finds that the organic sulfur-containing compound is an indispensable part for maintaining normal life activities of microorganisms, animals and plants; methionine and vitamin H are natural products containing a thioether structure; allicin with antibacterial, insecticidal and anticancer activities, cyclobrasinine with antifungal activity, epicocin with significant anti-HIV activity and the like are organic sulfur-containing compounds with a thioether structure separated from nature; penicillin and cephalosporin medicaments both contain thioether structural units; in the published medicines and prescription medicines of Top200 in the whole United states counted in 2011, the proportion of sulfur-containing medicines is as high as about 25%.

In the agricultural bioactive compounds, the sulfoxide/sulfone derivatives have various biological activities such as good insecticidal activity, good sterilization activity, good weeding activity, good plant growth regulation activity and the like, and show great application values in agriculture. At the same time, sulfoxide/sulfone compounds are also important drugs for the treatment of many diseases. Through structural modification, the sulfoxide/sulfone compounds can generate biological activities of resisting tumor, virus, HIV-1, acid, ulcer, tuberculosis and the like.

Disclosure of Invention

The invention aims to introduce some thioether, sulfoxide and sulfone molecules with heterocyclic structures into a dihydroartemisinin structure, design and synthesize thioether, sulfoxide and sulfone derivatives of dihydroartemisinin with novel structures, perform biological activity research, hope to obtain lead molecules with certain biological activity, and lay a foundation for the wide research and application development of artemisinin compounds.

Through research, the invention provides the following technical scheme:

1. thioether, sulfoxide and sulfone derivatives of dihydroartemisinin shown as formula I or racemate, stereoisomer, tautomer, oxynitride and pharmaceutically acceptable salt thereof:

in the formula I, n is 1 or 2, when m is 0, Y is

When n is 2, m is 0, Y is

n is 1 or 2, when m is 1 or 2, Y is

R₁、R₂And R₃Each independently is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, amino, C1-C6 alkylamino, or C1-C6 alkylamido.

Further, R₁、R₂And R₃Each independently is H, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, amino, C1-C3 alkylamino, or C1-C3 alkylamido.

Further, R₁、R₂And R₃Independently H, methoxy, amino or acetylamino.

Further, when n is 1 or 2 and m is 0, Y is

n is 2, when m is 0, Y is

n is 1 or 2, when m is 1 or 2, Y is

2. The application of thioether, sulfoxide and sulfone derivatives of dihydroartemisinin shown in formula I or racemates, stereoisomers, tautomers, nitric oxides and pharmaceutically acceptable salts thereof in the preparation of antimalarial drugs.

Further, the antimalarial drug is a drug for resisting plasmodium falciparum or/and plasmodium berghei in an infrared phase.

3. The application of thioether, sulfoxide and sulfone derivatives of dihydroartemisinin shown in formula I or racemate, stereoisomer, tautomer, nitrogen oxide and pharmaceutically acceptable salt thereof in the preparation of medicaments for resisting leishmania.

Further, the anti-leishmanial agent is an anti-Leishmania donovani agent.

4. The application of thioether, sulfoxide and sulfone derivatives of dihydroartemisinin shown in the formula I or racemates, stereoisomers, tautomers, nitric oxides and pharmaceutically acceptable salts thereof in preparing anti-angiogenesis medicaments.

5. The application of thioether, sulfoxide and sulfone derivatives of dihydroartemisinin shown in formula I or racemates, stereoisomers, tautomers, nitric oxides and pharmaceutically acceptable salts thereof in preparing antitumor drugs.

Furthermore, the anti-tumor drug is a drug with K-ras/Wnt synthetic lethal activity.

Further, the tumor is colorectal cancer.

6. The application of thioether, sulfoxide and sulfone derivatives of dihydroartemisinin shown in formula I or racemates, stereoisomers, tautomers, nitric oxides and pharmaceutically acceptable salts thereof in preparing hypolipidemic medicaments.

Further, the hypolipidemic agent is a proprotein convertase subtilisin 9(PCSK9) inhibitor.

7. The application of thioether, sulfoxide and sulfone derivatives of dihydroartemisinin shown in the formula I or racemates, stereoisomers, tautomers, nitric oxides and pharmaceutically acceptable salts thereof in preparing Wnt signal channel agonists.

Further, the Wnt signaling pathway agonist is a Wnt/beta-catenin signaling pathway agonist.

The term "racemate" as used herein means, unless otherwise specified, an optically inactive organic substance composed of equal amounts of enantiomers. "stereoisomers" refers to molecules that have the same atomic composition and bonding, but differ in the arrangement of the atoms in three-dimensional space. "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. "Nitrogen oxide" means a tertiary nitrogen with an oxygen atom forming⁺N-O^-Organic matter of the structural unit. The "pharmaceutically acceptable salt" may be an acidic salt or a basic salt, such as an inorganic acid salt, an organic acid salt, an inorganic base salt or an organic base salt.

The invention has the beneficial effects that: the invention introduces some thioether, sulfoxide and sulfone molecules with heterocyclic structures into a dihydroartemisinin structure, designs and synthesizes thioether, sulfoxide and sulfone derivatives of dihydroartemisinin with novel structures, and biological activity test results show that the thioether, sulfoxide and sulfone derivatives of dihydroartemisinin have various biological activities and have the potential of further developing into antimalarial drugs, anti-leishmanial drugs, anti-angiogenesis drugs, anti-tumor drugs, blood fat reduction drugs or/and Wnt signal path agonists.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, preferred embodiments of the present invention will be described in detail below.

The main reagents and specifications used in the preferred embodiment: dihydroartemisinin (pharmaceutical ltd, AR, waring, china, warrior, chongqing); 2-bromoethanol, 3-bromo-1-propanol (Shanghaineri Fine chemical Co., Ltd., AR); 46.5% boron trifluoride diethyl etherate (BF)₃·Et₂O) (shanghai crystal pure reagents ltd, AR); 5-methoxy-2-mercapto-1H-benzimidazole (Shanghai Dairy Fine Chemicals, Inc., 98%); m-chloroperoxybenzoic acid (Chengdu Ester pharmaceutical technology, Inc., AR); 15% peracetic acid (two-component) (adult municipality dragon chemical reagent factory, AR); 2-mercaptobenzimidazole, 2-mercaptobenzoxazole, 2-amino-5-mercapto-1, 3, 4-thiadiazole and 2-acetamido-5-mercapto-1, 3, 4-thiadiazole are all self-made; the other reagents are all commercial chemical pure or analytical pure products and are directly used without purification.

The main instruments and models used in the preferred embodiment: a precise micro melting point tester (X-6, Beijing Fukai Instrument Co., Ltd.); digital automatic polarimeters (WZZ-2S, Shanghai precision scientific instruments, Inc.); superconducting nuclear magnetic resonance spectrometer (AV-300, Bruker, Switzerland); high resolution mass spectrometer (HR ESI MS) (Varian7.0T, Varian, USA).