阅读说明：本技术 二氢青蒿素嘧啶类衍生物及其应用 (Dihydroartemisinin pyrimidine derivative and application thereof ) 是由 杨大成 刘建 范莉 张书虹 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或式II所示的二氢青蒿素嘧啶类衍生物,式中n为1或2；Y<Sub>1</Sub>为<Image he="229" wi="512" file="DDA0002216825260000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>或<Image he="230" wi="216" file="DDA0002216825260000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>Y<Sub>2</Sub>为<Image he="222" wi="217" file="DDA0002216825260000013.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>或<Image he="236" wi="212" file="DDA0002216825260000014.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>R<Sub>1</Sub>为H、C1-C6烷基或C1-C6羟烷基；R<Sub>2</Sub>、R<Sub>3</Sub>各自独立地为羟基、氨基、C1-C6烷基、C1-C6羟烷基或C1-C6烷胺基；还公开了所述二氢青蒿素嘧啶类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="186" wi="700" file="DDA0002216825260000015.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a dihydroartemisinin pyrimidine derivative shown in a formula I or a formula II, wherein n is 1 or 2; y is 1 Is composed of Or Y 2 Is composed of Or R 1 Is H, C1-C6 alkyl or C1-C6 hydroxyalkyl; r 2 、R 3 Each independently is hydroxy, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 alkylamino; also discloses the application of the dihydroartemisinin pyrimidine derivatives in preparing antimalarial drugs, leishmanial drugs, anti-angiogenesis drugs, antitumor drugs, hypolipidemic drugs or/and Wnt signal pathway agonists.)

1. Dihydroartemisinin pyrimidine derivatives shown in formula I or formula II, or racemates, stereoisomers, tautomers, nitrogen oxides and pharmaceutically acceptable salts thereof:

in formula I or formula II, n is 1 or 2;

Y₁is composed of

R₁Is H, C1-C6 alkyl or C1-C6 hydroxyalkyl; r₂、R₃Each independently is hydroxy, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 alkylamino.

2. The dihydroartemisinin pyrimidine derivative or its racemate, stereoisomer, tautomer, nitroxide, pharmaceutically acceptable salt thereof according to claim 1, wherein: r₁Is H, C1-C3 alkyl or C1-C3 hydroxyalkyl; r₂Is hydroxy or amino; r₃Is C1-C3 alkyl or amino.

3. The dihydroartemisinin pyrimidine derivative or its racemate, stereoisomer, tautomer, nitroxide, pharmaceutically acceptable salt thereof according to claim 2, wherein: r₁Is H, methyl or hydroxymethyl; r₂Is hydroxy or amino; r₃Is methyl or amino.

4. A dihydroartemisinin pyrimidine derivative or its racemate, stereoisomer, tautomer, nitroxide, pharmaceutically acceptable salt thereof, as claimed in claim 3, wherein: the dihydroartemisinin pyrimidine derivative shown in the formula I or the formula II is any one of the following compounds:

5. the use of a dihydroartemisinin pyrimidine derivative or its racemate, stereoisomer, tautomer, nitroxide, pharmaceutically acceptable salt as claimed in claim 1 for the preparation of antimalarial drugs.

6. Use of a dihydroartemisinin pyrimidine derivative or its racemate, stereoisomer, tautomer, nitroxide, pharmaceutically acceptable salt according to claim 1 for the preparation of a medicament against leishmania.

7. The use of a dihydroartemisinin pyrimidine derivative or its racemate, stereoisomer, tautomer, nitroxide, pharmaceutically acceptable salt according to claim 1 for the preparation of an antiangiogenic medicament.

8. The use of a dihydroartemisinin pyrimidine derivative or its racemate, stereoisomer, tautomer, nitroxide or pharmaceutically acceptable salt as claimed in claim 1 in the preparation of an antitumor medicament.

9. The use of a dihydroartemisinin pyrimidine derivative or its racemate, stereoisomer, tautomer, nitroxide or pharmaceutically acceptable salt as claimed in claim 1 in the preparation of hypolipidemic drugs.

10. The use of a dihydroartemisinin pyrimidine derivative or its racemate, stereoisomer, tautomer, nitroxide or pharmaceutically acceptable salt as claimed in claim 1 in the preparation of a Wnt signaling pathway agonist.

Technical Field

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

Background

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

The pyrimidine compounds are important substances in life activities and widely exist in human bodies and organisms, for example, 3 pyrimidine-containing structures, namely uracil, cytosine and thymine, exist in the most common 5 nitrogen-containing basic components of nucleic acid. Uracil is a natural nucleoside, has a pyrimidine ring structure, participates in glycogen synthesis, and contributes to improving the hypoxia tolerance of cells; it is also a component of nucleic acids that make up animal cells and can raise the level of body antibodies. Animal experiments show that the combination of uracil and inosine can promote the metabolism of cardiac muscle cells, accelerate the biosynthesis of protein and nucleic acid and energy generation, and promote and improve the metabolism of brain cells. Uracil and its derivatives can also be used to block gene synthesis in various cancer cells and viruses, and to treat cancer and viral-induced diseases. Cytosine is used as pyrimidine nucleoside, is mainly used as intermediate for producing antitumor and antiviral medicine and is the main material for preparing cytarabine, cyclocytidine, cytidine triphosphate, cytidine diphosphate, etc.

The pyrimidine (sulfur) ether compounds are acetolactate synthase inhibitors after sulfonylurea and fused sulfonamide herbicides, and are a great hot spot in herbicide research. 4-amino-6-hydroxy-2-mercaptopyrimidine can be used as a medical intermediate and is commonly used for producing 6-mercaptopurine which is an anti-malignant tumor drug. The methyl thiouracil can be used as an antithyroid drug and is a main intermediate of a cardiovascular drug dipyridamole.

Allopurinol is a xanthine oxidase inhibitor, and is mainly used for treating gout and preventing gouty nephropathy, secondary hyperuricemia and severe epilepsy. In addition, allopurinol is also found to be effective in treating diseases such as chronic heart failure, progressive muscular dystrophy, nonbacterial prostatitis, 5-fluorouracil, medicinal cystitis caused by bladder tumor, kidney diseases and the like.

Disclosure of Invention

The invention aims to combine dihydroartemisinin and pyrimidine compounds, design and synthesize dihydroartemisinin pyrimidine derivatives with novel structures, carry out 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. dihydroartemisinin pyrimidine derivatives shown in formula I or formula II, or racemates, stereoisomers, tautomers, nitrogen oxides and pharmaceutically acceptable salts thereof:

in formula I or formula II, n is 1 or 2;

Y₁is composed of

Y₂Is composed of

R₁Is H, C1-C6 alkyl or C1-C6 hydroxyalkyl; r₂、R₃Each independently is hydroxy, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 alkylamino.

Further, R₁Is H, C1-C3 alkyl or C1-C3 hydroxyalkyl; r₂Is hydroxy or amino; r₃Is C1-C3 alkyl or amino.

Further, R₁Is H, methyl or hydroxymethyl; r₂Is hydroxy or amino; r₃Is methyl or amino.

Further, the dihydroartemisinin pyrimidine derivative shown in the formula I or the formula II is any one of the following compounds:

2. application of dihydroartemisinin pyrimidine derivatives shown in formula I or formula II or racemates, stereoisomers, tautomers, nitric oxides and pharmaceutically acceptable salts thereof in preparation of antimalarial drugs.

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

3. Application of dihydroartemisinin pyrimidine derivatives shown in formula I or formula II or racemates, stereoisomers, tautomers, nitric oxides and pharmaceutically acceptable salts thereof in preparation of anti-leishmanial drugs.

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

4. Application of dihydroartemisinin pyrimidine derivatives shown in formula I or formula II or racemates, stereoisomers, tautomers, nitric oxides and pharmaceutically acceptable salts thereof in preparation of anti-angiogenesis drugs.

5. Application of dihydroartemisinin pyrimidine derivatives shown in formula I or formula II or racemates, stereoisomers, tautomers, nitric oxides and pharmaceutically acceptable salts thereof in preparation of antitumor drugs.

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

Further, the tumor is colorectal cancer.

6. An application of dihydroartemisinin pyrimidine derivatives shown in formula I or formula II or racemates, stereoisomers, tautomers, nitrogen oxides and pharmaceutically acceptable salts thereof in preparing a blood fat reducing medicine.

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

7. Application of dihydroartemisinin pyrimidine derivatives shown in formula I or formula II or racemates, stereoisomers, tautomers, nitric oxides and pharmaceutically acceptable salts thereof in preparation of Wnt signal pathway 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 dihydroartemisinin pyrimidine derivatives with novel structures are designed and synthesized by combining dihydroartemisinin and pyrimidine compounds, and the biological activity test result shows that the dihydroartemisinin pyrimidine derivatives have various biological activities and have the potential of being further developed into antimalarial drugs, leishmania resistant drugs, angiogenesis resistant drugs, antitumor drugs, blood fat lowering drugs or/and Wnt signal channel 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); uracil, thymine, methylthiouracil, 4, 6-diamino-2-mercaptopyrimidine, 6-amino-2-thiouracil (Shanghaineri Fine Chemicals Co., Ltd., 98%); 5-hydroxymethyluracil (homemade); allopurinol (given by southwest synthetic pharmaceuticals, inc.); 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).