WO2020228463A1 - 抗白血病硒代那可丁衍生物的制备方法及其应用 - Google Patents

抗白血病硒代那可丁衍生物的制备方法及其应用 Download PDF

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WO2020228463A1
WO2020228463A1 PCT/CN2020/084517 CN2020084517W WO2020228463A1 WO 2020228463 A1 WO2020228463 A1 WO 2020228463A1 CN 2020084517 W CN2020084517 W CN 2020084517W WO 2020228463 A1 WO2020228463 A1 WO 2020228463A1
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substituted
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selenonarcotin
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王卫
张永强
阴倩倩
刘传绪
潘鹏
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East China University of Science and Technology
ShanghaiTech University
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ShanghaiTech University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

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  • the invention relates to the field of medicine, in particular to a preparation method and application of an anti-leukemia selenomatine derivative.
  • Leukemia also known as blood cancer, is a malignant proliferative disease of hematopoietic stem cells.
  • the patient’s bone marrow hematopoietic system produces a large number of immature, non-working white blood cells, resulting in a reduction of normal platelets, red blood cells, and white blood cells.
  • These undeveloped white blood cells are called leukemia cells.
  • leukemia cells According to the degree of differentiation of leukemia cells and the length of the natural course, it can be divided into acute and chronic leukemia. According to the series of diseased cells, it is mainly divided into myeloid and lymphoid lines.
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • Chemotherapy drugs as an effective way to treat leukemia, are widely used clinically.
  • vincristine for the treatment of various acute and chronic leukemias
  • cytarabine for the treatment of acute leukemias.
  • methotrexate for the treatment of acute leukemias.
  • the toxic and side effects of these drugs have seriously affected the quality of life of leukemia patients.
  • targeted drugs with low side effects have shown unique advantages in the treatment of leukemia.
  • increasing drug resistance has become the bottleneck of its clinical application. Therefore, there is an urgent need to develop anti-leukemia drugs with high efficacy, low toxicity and high therapeutic index.
  • the invention discloses a selenonarcotin derivative that can be used as a leukemia therapeutic drug, and a preparation method and application thereof.
  • Noscapine is a phthalide tetrahydroisoquinoline alkaloid isolated from opium poppy. It has a simple structure, rich natural content, and low price. It was first used clinically as an over-the-counter cough medicine and is safe and reliable. Can be administered orally. It was discovered in 1998 to show certain inhibitory activity against various solid tumors, such as lung cancer and colon cancer. At the same time, it can penetrate the blood-brain barrier for the treatment of brain glioma.
  • selenium As a trace element necessary for human body, selenium has very important physiological functions. Appropriate intake of trace selenium can effectively improve the body's antioxidant capacity and anti-cancer capacity, and enhance immune function. In recent years, many studies have shown that the introduction of selenium into anti-tumor compounds can play a synergistic effect and effectively improve the anti-tumor activity of lead compounds.
  • this study synthesized a series of narcotine derivatives with 9 selenoses through a semi-synthetic method. These derivatives show excellent inhibitory activity on various leukemia cells and are expected to develop high-efficiency and low-toxic leukemia therapeutic drugs.
  • the first aspect of the present invention discloses a selenonarcotine derivative, the general structural formula of the selenonarcotine derivative is shown in general formula i or general formula ii:
  • the R 1 or R 2 group is alkyl, cycloalkyl, aryl, heteroaryl, oxyalkyl, ester alkyl, allyl, propargyl or cyano.
  • the aryl group is phenyl, substituted phenyl, biphenyl, naphthyl or substituted naphthyl; and the heteroaryl group is pyridyl, substituted pyridyl, thienyl, substituted thiophene, furanyl, or substituted furan.
  • pyrrolyl substituted pyrrolyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl, benzothiazolyl, substituted benzothiazolyl, indolyl, substituted indolyl, benzene Aminoimidazolyl, substituted imidazolyl, benzoxazolyl, substituted benzoxazolyl, imidazolyl, substituted imidazolyl, oxazolyl, substituted oxazolyl, thiazolyl or substituted thiazolyl;
  • the alkyl group is a C1-C6 alkyl group or a deuterated alkyl group
  • the cycloalkyl group is a C1-C8 cycloalkyl group or a deuterated cycloalkyl group;
  • the aryl group is a substituted phenyl group.
  • the selenonarcotin derivative is the following compound:
  • the second aspect of the present invention discloses a method for preparing the above-mentioned selenonarcotin derivative.
  • the general structural formula of the selenonarcotin derivative is shown in the general formula i, and includes the following steps:
  • the hydroxymethylation reaction, the chlorination reaction, the nucleophilic substitution reaction involving potassium selenocyanide, the in-situ reduction of selenol and the nucleophilic substitution reaction are carried out in sequence to obtain the structure
  • a method for preparing selenonate derivatives which includes the following steps:
  • a method for preparing selenonate derivatives which includes the following steps:
  • the third aspect of the present invention discloses the application of the above-mentioned selenonarcotin derivatives in the field of leukemia.
  • the fourth aspect of the present invention discloses a medicine for treating leukemia, which is characterized in that the active ingredient of the medicine is the selenonarcotin derivative according to claim 1.
  • the present invention has the following significant advantages and effects:
  • the present invention synthesizes a series of 9-seleno-selenium narcotine derivatives through a semi-synthetic method.
  • the synthetic route is short, the experimental operation is simple, and the yield effect is good; the seleno- narcotine derivatives obtained by the preparation method
  • the compound shows excellent inhibitory activity on various leukemia cells, and can be used to prepare high-efficiency and low-toxic leukemia therapeutic drugs.
  • the selenonarcotin derivatives in the present invention are the following compounds:
  • a method for preparing selenonarcotin derivatives is disclosed, and the design route includes the following steps:
  • a method for preparing selenonarcotin derivatives is disclosed, and the design route includes the following steps:
  • Example 4-9 The synthesis of compound S4-S9 is the same as that of S3.
  • Example 14-22 The synthesis method of compound S14-S22 is the same as the synthesis method of S13.
  • Sample preparation use DMSO (purchased from Merck) to dissolve the S1-S26 synthesized in the above example and narcotin (Tichai (Shanghai) Chemical Industry Development Co., Ltd.) (as a negative control), and add PBS to make 1000mg /mL solution or uniform suspension, and then diluted with PBS containing DMSO;
  • This experiment uses the CCK-8 method. Add 100 mL of a cell suspension of a human leukemia cell line with a concentration of 7-8 ⁇ 10 3 cells/mL to each well of a 96-well plate, and place it in a 37°C, 5% CO 2 incubator. After 24 hours of incubation, 100 mL of sample solution was added to each well, and three multiple wells were set up. 37°C, 5% CO 2 acted for 48 hours. Then add 20 mL of CCK-8 solution to each well and place in the incubator for 2-4 hours. Then use a full-wavelength multifunctional microplate reader to measure the OD value at 450nm.

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  • Life Sciences & Earth Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明涉及医药领域，具体涉及一种抗白血病硒代那可丁衍生物的制备方法及其应用。所述硒代那可丁衍生物的结构通式如通式i或通式ii所示，本发明通过半合成的方法，合成了一系列9位硒代的那可丁衍生物，该合成路线短，实验操作简单，且收率效果好；该制备方法得到的硒代的那可丁衍生物对各种白血病细胞显示出优异的抑制活性，可用于制备高效且低毒的白血病治疗药物，(i), (ii) 所述R1或R2基团为烷基、环烷基、芳基、杂芳基、氧烷基、酯烷基、烯丙基、炔丙基或氰基。

Description

抗白血病硒代那可丁衍生物的制备方法及其应用 技术领域
本发明涉及医药领域，具体涉及一种抗白血病硒代那可丁衍生物的制备方法及其应用。
背景技术
白血病，亦称作血癌，是一种造血干细胞的恶性增生性病变。病人的骨髓造血系统产生大量不成熟、无法正常工作的白细胞，造成正常的血小板、红细胞、白细胞减少。这些尚未发育完全的白细胞，被称为白血病细胞。根据白血病细胞的分化程度、自然病程的长短可分为急、慢性白血病。按照病变细胞系列分类，主要分为髓系和淋巴系。临床常见发病类型主要有四种，包括急性淋巴细胞白血病(ALL)，急性髓性白血病(AML)，慢性淋巴细胞白血病(CLL)和慢性髓性白血病(CML)。调查表明，在我国，白血病导致的死亡率，男性居第六位，女性居第八位，由此可见白血病严重威胁着人类的健康。
化疗药物，作为治疗白血病的有效方式，在临床上广泛使用。例如治疗各种急慢性白血病的长春新碱，用于治疗急性白血病的阿糖胞苷和甲氨喋呤等。然而该类药物的毒副作用严重影响了白血病患者的生存质量。近年来，靶向药物，毒副作用小，在治疗白血病种显示出独特的优势，然而日益增加耐药性成为其临床应用的瓶颈。因此亟需发展高效低毒，治疗指数高的抗白血病药物。
发明内容
本发明公开了一种能够用于白血病治疗药物的硒代那可丁衍生物及其制备方法和应用。
设计思路如下：
那可丁(Noscapine)是从罂粟中分离得来的苯酞四氢异喹啉类生物碱，其结构简单，自然界含量丰富，价格低廉，最早在临床上作为非处方止咳药使用，安全可靠，可口服给药。1998年被发现对各种实体瘤，如肺癌和结肠癌等，表现出一定的抑制活性。同时，可以透过血脑屏障，用于脑部神经胶质瘤的治疗。初步研究表明，其作用机制为微管蛋白抑制剂，与微管蛋白相结合，干扰微管动态平衡，致使细胞停滞于有丝分裂G2/M期而凋亡，产生抗肿瘤作用。然而该类化合物在白血病治疗中的应用鲜见报道。
硒作为一种人体所必须的微量元素，有着非常重要的生理功能。适当的摄取微量硒元素能够有效提高机体的抗氧化能力和抗癌能力、增强免疫功能。近年来，诸多研究表明，将硒元素引入到抗肿瘤化合物中，可起到协同增效的作用，有效提高先导化合物的抗肿瘤活性。
鉴于此，本研究通过半合成的方法，合成了一系列9位硒代的那可丁衍生物。这些衍生物对各种白血病细胞显示出优异的抑制活性，有望开发高效低毒的白血病治疗药物。
具体的，本发明的技术方案如下：
本发明第一个方面公开了一种硒代那可丁衍生物，所述硒代那可丁衍生物的结构通式如通式i或通式ii所示：
Figure PCTCN2020084517-appb-000001
所述R 1或R 2基团为烷基、环烷基、芳基、杂芳基、氧烷基、酯烷基、烯丙基、炔丙基或氰基。
优选地，所述芳基为苯基、取代苯基、联苯基、萘基或取代萘基；所述杂芳基为吡啶基、取代吡啶基、噻吩基、取代噻吩、呋喃基、取代呋喃基、吡咯基、取代吡咯基、喹啉基、取代喹啉基、异喹啉基、取代异喹啉基、苯并噻唑基、取代苯并噻唑基、吲哚基、取代吲哚基、苯并咪唑基、取代咪唑基、苯并恶唑基、取代苯并恶唑基、咪唑基、取代咪唑基、恶唑基、取代恶唑基、噻唑基或取代噻唑基；
所述烷基为C1-C6烷基或氘代烷基；
所述环烷基为C1-C8环烷基或氘代环烷基；
更优选的，所述芳基为取代苯基。
进一步优选，所述硒代那可丁衍生物为以下化合物：
Figure PCTCN2020084517-appb-000002
Figure PCTCN2020084517-appb-000003
Figure PCTCN2020084517-appb-000004
Figure PCTCN2020084517-appb-000005
Figure PCTCN2020084517-appb-000006
Figure PCTCN2020084517-appb-000007
Figure PCTCN2020084517-appb-000008
本发明第二个方面公开了一种制备上述的硒代那可丁衍生物的方法，所述硒代那可丁衍生物的结构通式如通式i所示，包括以下步骤：
以结构式如式I所示的化合物为底物，依次进行羟甲基化反应、氯代反应、硒氰化钾参与的亲核取代反应、硒醇原位还原生成和亲核取代反应，得到结构通式如通式i所示的硒代那可丁衍生物；
以结构式如式I所示的化合物为底物，依次进行溴代反应、氨基化反应、重氮化反应、硒氰化钾参与的亲核取代反应、硒醇原位还原生成和亲核取代反应，即得到结构通式如通式ii所示的硒代那可丁衍生物，或
以结构式如式I所示的化合物为底物，直接与二硒化物进行自由基加成反应，即得到结构通式如通式ii所示的硒代那可丁衍生物；
Figure PCTCN2020084517-appb-000009
本发明的一优选实施例中，公开了一种制备硒代那可丁衍生物的方法，包括以下步骤：
Figure PCTCN2020084517-appb-000010
本发明的一优选实施例中，公开了一种制备硒代那可丁衍生物的方法，包括以下步骤：
Figure PCTCN2020084517-appb-000011
具体的，步骤如下：
1)化合物Ⅰ在浓盐酸的作用下，发生羟甲基化反应，得到化合物Ⅱ，收率98％。2)化合物Ⅱ在室温下，与二氯亚砜反应，得氯代产物Ⅲ，收率100％。
3)化合物Ⅲ与硒氰化钾发生亲核取代反应，得到化合物Ⅳ(也就是化合物S1)，收率99％。
4)化合物Ⅳ(也就是化合物S1)经硼氢化钠还原后，继续与卤代烷烃发生亲核取代反应得到化合物Ⅴ(也就是化合物S3-S22)，收率40-72％，
Figure PCTCN2020084517-appb-000012
5)化合物Ⅲ在48％氢溴酸和溴水作用下，得到9-溴那可丁Ⅵ，收率95％。
6)化合物Ⅵ经氨基化反应得到目标产物VII，收率80％。
7)化合物Ⅶ经重氮化反应，硒氰化钾参与的亲核取代反应得目标产物VIII，收率50％。
8)化合物ⅥII经硼氢化钠还原后，继续与碘甲烷发生亲核取代反应，得到化合物S24，收率68％。
9)化合物ⅥII经硼氢化钠还原后，继续与三氟甲基三甲基硅烷发生亲核取代反应，得到化合物S25，收率71％。
10)化合物Ⅰ在过硫酸钾作用下，与二苯基二硒醚发生自由基加成反应，得到化合物S26，收率95％。
本发明第三个方面公开了上述的硒代那可丁衍生物在白血病领域中的应用。
本发明第四个方面公开了一种治疗白血病的药物，其特征在于，所述药物的活性成分为权利要求1所述的硒代那可丁衍生物。
在符合本领域常识的基础上，上述各优选条件，可任意组合，而不超出本发明的构思与保护范围。
本发明相对于现有技术具有如下的显著优点及效果：
本发明通过半合成的方法，合成了一系列9位硒代的那可丁衍生物，该合成路线短，实验操作简单，且收率效果好；该制备方法得到的硒代的那可丁衍生物对各种白血病细胞显示出优异的抑制活性，可用于制备高效且低毒的白血病治疗药物。
具体实施方式
下面结合附图和实施例对本发明的技术方案进行详细描述，但并不因此将本发明限制在所述的实施例范围之中。
下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。本发明所用试剂和原料均市售可得。
本发明中的硒代那可丁衍生物为以下化合物：
Figure PCTCN2020084517-appb-000013
Figure PCTCN2020084517-appb-000014
Figure PCTCN2020084517-appb-000015
Figure PCTCN2020084517-appb-000016
Figure PCTCN2020084517-appb-000017
Figure PCTCN2020084517-appb-000018
本发明的一些优选实施例中，公开了一种制备硒代那可丁衍生物的方法，设计路线包括以下步骤：
Figure PCTCN2020084517-appb-000019
本发明的一些优选实施例中，公开了一种制备硒代那可丁衍生物的方法，设计路线包括以下步骤：
Figure PCTCN2020084517-appb-000020
详细描述如下：
实施例1
1)化合物Ⅱ的合成：
称取1.8g那可丁盐酸盐溶于50mL浓盐酸中，室温分批加入4g多聚甲醛，加毕，50℃搅拌2小时。反应结束后，冷却，滴加氨水调pH至10，二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，得1.9g无色油状液体，产率98％。 1H NMR(400MHz,CDCl 3)δ6.91(d,J＝8.3Hz,1H),6.14(d,J＝8.2Hz,1H),5.88(s,2H),5.45(d,J＝4.3Hz,1H),5.23(s,1H),4.56(s,2H),4.31(d,J＝4.3Hz,1H),4.01(s,3H),3.92(s,3H),3.79(s,3H),2.70-2.54(m,2H),2.46(s, 3H),2.39-2.27(m,1H),1.90-1.86(m,1H)。
2)化合物Ⅲ的合成：
将1.62g化合物Ⅱ溶于20mL二氯甲烷中，0℃下缓慢滴加0.5mL二氯亚砜，滴加完毕后，缓慢升至室温，搅拌2小时，滴加氨水调pH至10，二氯甲烷萃取三次，合并有机相，有机相经无水硫酸钠干燥，过滤，浓缩，得目标产物1.7g，产率100％。
3)化合物S1的合成：
称取1.38g化合物Ⅲ加入到50mL乙腈中，再加入0.86g KSeCN，80℃下，5分钟后停止反应，快速冷却至室温，加水稀释，以乙酸乙酯萃取三次，有机相以饱和食盐水洗，经无水硫酸钠干燥，过滤，浓缩，得目标产物1.6g，产率99％。 1H NMR(400MHz,CDCl 3)δ7.01(d,J＝8.3Hz,1H),6.20(d,J＝8.2Hz,1H),6.05–5.93(m,2H),5.53(d,J＝4.2Hz,1H),4.41(t,J＝8.6Hz,2H),4.18(d,J＝11.4Hz,1H),4.09(s,3H),4.04(s,3H),3.86(s,3H),2.82–2.64(m,1H),2.53(d,J＝7.0Hz,3H),2.52–2.37(m,2H),1.90(ddd,J＝15.3,8.0,4.6Hz,1H)。
实施例2
化合物S2的合成：
Figure PCTCN2020084517-appb-000021
称取0.26g化合物Ⅳ于反应瓶中，0℃下，加入5mL无水四氢呋喃和0.14g TMSCF 3，缓慢滴加0.1mL四丁基氟化铵的四氢呋喃溶液(1mol/L),后转移至室温反应2小时，反应完全后，加水稀释，以乙酸乙酯萃取三次，有机相以饱和食盐水洗，经无水硫酸钠干燥，过滤，浓缩，所得粗产物经硅胶柱层析纯化，得0.20g目标产物，产率69％。 1H NMR(400MHz,CDCl 3)δ6.95(d,J＝8.2Hz,1H),6.04(d,J＝8.2Hz,1H),5.98(d,J＝0.7Hz,2H),5.50(d,J＝4.2Hz,1H),4.39(d,J＝4.3Hz,1H),4.27(d,J＝11.6Hz,1H),4.12(d,J＝11.6Hz,1H),4.09(s,3H),4.02(s,3H),3.86(s,3H),2.76–2.64(m,1H),2.53(s,3H),2.51–2.32(m,2H),1.88–1.73(m,1H)。
实施例3
化合物S3的合成：
Figure PCTCN2020084517-appb-000022
称取0.11g化合物Ⅳ与0.015g硼氢化钠同时加入到反应瓶中，氮气保护下加入1mL无水乙醇，室温搅拌30分钟后，加入碘甲烷0.035g，室温继续反应2小时，反应完全后，加水稀释，以乙酸乙酯萃取三次，有机相以饱和食盐水洗，经无水硫酸钠干燥后，过滤，浓缩，所得粗产物经硅胶柱层析纯化(乙酸乙酯：石油醚＝1：3)，得0.071g目标产物，产率68％。 1H NMR(400MHz,CDCl 3)δ6.89(d,J＝8.3Hz,1H),6.01(d,J＝8.2Hz,1H),5.88(dd,J＝7.3,1.3Hz,2H),5.46(d,J＝4.2Hz,1H),4.34(d,J＝4.2Hz,1H),4.02(s,3H),3.94(s,3H),3.79(s,3H),3.66–3.58(m,3H),2.65–2.55(m,1H),2.47(s,4H),2.33–2.25(m,1H),1.97(s,3H),1.76(ddd,J＝13.5,6.5,3.1Hz,1H)。
实施例4-9：化合物S4-S9的合成与S3的合成方法相同。
实施例10
化合物S10的合成：
Figure PCTCN2020084517-appb-000023
称取0.11g化合物Ⅳ(也就是化合物S1)与0.015g硼氢化钠同时加入到反应瓶中，氮气保护下加入5mL无水乙醇，室温搅拌30分钟后，加入溴甲基环丙烷0.042g，室温继续反应2小时，反应完全后，加水稀释，以乙酸乙酯萃取三次，有机相以饱和食盐水洗，经无水硫酸钠干燥后，过滤，浓缩，所得粗产物经硅胶柱层析纯化(乙酸乙酯：石油醚＝1：3)，得0.078g目标产物，产率72％。 1H NMR(400MHz,CDCl 3)δ6.92(d,J＝8.3Hz,1H),6.02(d,J＝7.2Hz,1H),5.89(dd,J＝7.6,1.3Hz,2H),5.47(d,J＝3.1Hz,1H),4.35(d,J＝4.0Hz,1H),4.02(s,3H),3.93(s,3H),3.79(s,3H),3.70(q,J＝11.7Hz,2H),2.61(m,1H),2.53(d,J＝7.2Hz,2H),2.47(s,3H),2.30(m,1H),1.78(m,2H),1.06–0.96(m,1H),0.59–0.48(m,2H),0.21–0.10(m,2H)。
实施例11
化合物S11的合成：
Figure PCTCN2020084517-appb-000024
称取0.11g化合物S1与0.015g硼氢化钠同时加入到反应瓶中，氮气保护下加入5mL无水乙醇，室温搅拌30分钟后，加入溴代环戊烷0.037g，室温继续反应2小时，反应完全后，加水稀释，用乙酸乙酯萃取三次，有机相以饱和食盐水洗，经无水硫酸钠干燥后，浓缩，所得粗产物经硅胶柱层析纯化(乙酸乙酯：石油醚＝1：3)，得0.078g目标产物，产率70％。 1H NMR(400MHz,CDCl 3)δ6.97(d,J＝8.3Hz,1H),6.04(d,J＝8.1Hz,1H),5.95(dd,J＝6.7,1.4Hz,2H),5.52(d,J＝3.7Hz,1H),4.41(d,J＝4.1Hz,1H),4.09(s,3H),4.01(s,3H),3.85(s,3H),3.78–3.64(m,2H),3.36–3.26(m,1H),2.63(s,1H),2.52(d,J＝8.0Hz,4H),2.35(t,J＝7.7Hz,1H),2.18–2.00(m,2H),1.89–1.53(m,10H).LRMS(ESI)Calcd.for C 28H 33NO 7Se[(M+H) +]576.1,found 576.1。
实施例12
化合物S12的合成：
Figure PCTCN2020084517-appb-000025
称取0.11g化合物S1与0.015g硼氢化钠同时加入到反应瓶中，氮气保护下加入5mL无水乙醇，室温搅拌30min后，加入溴代环庚烷0.044g，室温继续反应2小时，反应完全后，加水稀释，以乙酸乙酯萃取三次，有机相以饱和食盐水洗，经无水硫酸钠干燥后，浓缩，所得粗产物经硅胶柱层析纯化(乙酸乙酯：石油醚＝1：3)，得0.078g目标产物，产率42％。 1H NMR(400MHz,CDCl 3)δ6.97(d,J＝8.3Hz,1H),6.03(d,J＝8.2Hz,1H),5.96(dd,J＝7.2,1.4Hz,2H),5.52(d,J＝4.1Hz,1H),4.40 (d,J＝4.2Hz,1H),4.09(s,3H),4.02(s,3H),3.85(s,3H),3.70(dd,J＝22.5,11.6Hz,2H),3.19–3.09(m,1H),2.68–2.59(m,1H),2.53(s,4H),2.40–2.29(m,1H),2.19–2.07(m,2H),1.87–1.75(m,1H),1.70(tdd,J＝11.7,5.3,2.8Hz,4H),1.55(dd,J＝8.3,4.1Hz,3H),1.53–1.39(m,3H)； 13C NMR(100MHz,CDCl 3)δ168.3,152.1,147.6,146.5,141.1,139.2,133.4,130.8,120.0,118.5,117.9,117.8,112.3,100.8,81.9,63.3,62.3,60.9,59.5,56.8,49.6,46.3,44.5,41.7,36.1,36.1,28.1,28.0,26.9,23.7,16.7.LRMS(ESI)Calcd.for C 30H 39NO 7Se[(M+H) +]604.2,found 604.2。
实施例13
化合物S13的合成：
Figure PCTCN2020084517-appb-000026
称取0.11g化合物Ⅳ与0.015g硼氢化钠同时加入到反应瓶中，氮气保护下加入5mL无水乙醇，室温搅拌30分钟后，加入溴化苄0.043g，室温继续反应2小时，反应完全后，加水稀释，以乙酸乙酯萃取三次，有机相以饱和食盐水洗，经无水硫酸钠干燥后，浓缩，所得粗产物经硅胶柱层析纯化(乙酸乙酯：石油醚＝1：3)，得0.089g目标产物，产率75％。 1H NMR(400MHz,d 6-DMSO)δ7.34–7.26(m,4H),7.23–7.18(m,1H),6.89(d,J＝8.3Hz,1H),6.03(d,J＝8.2Hz,1H),5.95(dd,J＝10.6,1.4Hz,2H),5.51(d,J＝4.1Hz,1H),4.39(d,J＝4.2Hz,1H),4.08(s,3H),4.02(s,3H),3.88(dd,J＝23.2Hz,11.7Hz,2H),3.79(s,3H),3.70(dd,J＝29.3,11.7Hz,2H),2.65–2.54(m,1H),2.52(s,3H),2.47–2.23(m,2H),1.71(ddd,J＝15.5,8.7,4.5Hz,1H).LRMS(ESI)Calcd.for C 30H 32NO 7Se[(M+H) +]598.1,found 598.1。
实施例14-22：化合物S14-S22的合成方法与S13的合成方法相同。
实施例23
化合物S23的合成：
Figure PCTCN2020084517-appb-000027
称取0.28g化合物IV加入到10mL乙腈中，再加入0.12g KSCN，80℃下， 反应过夜，冷却至室温，加水稀释，以乙酸乙酯萃取三次(10mL×3)，有机相以饱和食盐水洗，经无水硫酸钠干燥，过滤，浓缩旋干，经柱层析分离得得0.21g目标产物，分离收率71％。 1H NMR(400MHz,CDCl 3)δ7.01(d,J＝8.3Hz,1H),6.20(d,J＝8.2Hz,1H),6.05–5.93(m,2H),5.53(d,J＝4.2Hz,1H),4.41(t,J＝8.6Hz,2H),4.18(d,J＝11.4Hz,1H),4.09(s,3H),4.04(s,3H),3.86(s,3H),2.82–2.64(m,1H),2.53(d,J＝7.0Hz,3H),2.52–2.37(m,2H),1.93–1.87(m,1H)。
实施例24
1)化合物Ⅵ的合成
称取4.0g那可丁盐酸盐溶于15mL HBr(48％)水溶液中，剧烈搅拌，室温下，将50mL新制溴水缓慢滴加到反应体系中，直到有黄色固体析出。滴加完毕后，反应1小时。反应结束后，用25％氨水调节pH至10，二氯甲烷萃取(50mL×3)，饱和食盐水洗，合并有机相，无水硫酸钠干燥，过滤，浓缩，经柱层析分离得到4.3g白色固体，产率90％。 1H NMR(400MHz,CDCl 3)δ7.02(d,J＝8.3Hz,1H),6.30(d,J＝8.2Hz,1H),6.02(s,2H),5.50(d,J＝4.5Hz,1H),4.34(d,J＝4.6Hz,1H),4.10(s,3H),3.98(s,3H),3.88(s,3H),2.67(m,2H),2.54–2.41(m,4H),1.96(m,1H)。
2)化合物Ⅶ的合成
向3g化合物Ⅱ的20mL无水DMSO的溶液中加入0.99g NaN 3，再加入0.87g Cu 2O和L-脯氨酸。加毕，将反应瓶置于100℃下反应24小时，TLC监测反应进程。反应完毕后，饱和氯化铵水溶液淬灭，后用二氯甲烷萃取三次，水洗，合并有机相，有机相经无水硫酸钠干燥，过滤，浓缩，经柱层析分离得到黄色固体2.1g，产率80％。 1H NMR(400MHz,CDCl 3)δ6.97(d,J＝8.3Hz,1H),6.16(d,J＝8.2Hz,1H),5.94(dd,J＝3.5,1.4Hz,2H),5.61(d,J＝4.0Hz,1H),4.38(d,J＝4.0Hz,1H),4.08(s,3H),3.88(s,3H),3.85(s,3H),3.30(s,2H),2.60–2.54(m,2H),2.51(s,3H),2.48–2.26(m,2H)。
3)化合物Ⅷ的合成
称取1.7g化合物Ⅲ加入到50mL H 2O中，0℃下缓慢滴加0.5mL浓盐酸于反应瓶中，再加入0.28g亚硝酸钠，搅拌30min后，以乙酸钠水溶液调节pH至6，随后加入0.58g KSeCN，室温搅拌反应3h，反应基本完全后，加入50mL乙酸乙酯，依次以饱和碳酸钠水溶液和水洗，有机相经无水硫酸钠干燥，过滤，浓缩，经柱层析分离得到1.0g白色固体，产率50％。
4)化合物S24的合成
Figure PCTCN2020084517-appb-000028
称取0.52g化合物Ⅷ与76mg硼氢化钠同时加入到反应瓶中，氮气保护下加入5mL无水乙醇，室温搅拌30min后，加入碘甲烷0.035g，室温继续反应2小时，反应完全后，加水稀释，以乙酸乙酯萃取三次，有机相以饱和食盐水洗，经无水硫酸钠干燥，过滤，浓缩，所得粗产物经硅胶柱层析纯化，得0.36g目标产物，产率68％。 1H NMR(400MHz,CDCl 3)δ6.93(d,J＝8.2Hz,1H),6.09(d,J＝8.0Hz,1H),6.01(dd,J＝5.3,1.2Hz,2H),5.50(d,J＝4.2Hz,1H),4.39(d,J＝4.2Hz,1H),4.10(s,3H),4.03(s,3H),3.86(s,3H),2.91-2.81(m,1H),2.78-2.65(m,1H),2.55(s,3H),2.36(m,J＝8.3Hz,1H),2.22–2.13(m,3H),1.88(s,1H)。
实施例25
化合物S25的合成：
Figure PCTCN2020084517-appb-000029
称取0.26g化合物Ⅷ于反应瓶中，0℃下，加入5mL无水THF和0.14g TMSCF 3，缓慢滴加0.1mL四丁基氟化铵四氢呋喃溶液(1mol/L)，后转移至室温反应2小时，反应完全后，加水稀释，以乙酸乙酯萃取三次，有机相以饱和食盐水洗，经无水硫酸钠干燥，过滤，浓缩，所得粗产物经硅胶柱层析纯化，得0.20g目标产物，产率71％。 1H NMR(400MHz,CDCl 3)δ6.91(d,J＝8.2Hz,1H),6.15–5.97(m,3H),5.49(d,J＝4.2Hz,1H),4.41(d,J＝4.2Hz,1H),4.11(s,3H),4.09(s,3H),3.85(s,3H),2.94–2.77(m,1H),2.75–2.64(m,1H),2.54(s,3H),2.40–2.26(m,1H),1.99–1.86(m,1H)。
实施例26
化合物S26的合成：
Figure PCTCN2020084517-appb-000030
称取0.41g化合物Ⅰ于反应瓶中，加入0.088mL三氟乙酸(TFA)、0.04g二苯基二硒醚和0.11g K 2S 2O 8，室温反应16小时，反应完全后，加水搅拌30min后，加水稀释，以乙酸乙酯萃取三次，有机相以饱和食盐水洗，经无水硫酸钠干燥，过滤，浓缩，得0.54g目标产物，产率95％。 1H NMR(400MHz,CDCl 3)δ7.32–7.17(m,7H),6.68(d,J＝8.3Hz,1H),6.09(d,J＝8.3Hz,1H),6.00(dd,J＝14.8,1.2Hz,2H),5.49(d,J＝4.2Hz,1H),4.40(d,J＝4.2Hz,1H),4.08(d,J＝1.5Hz,6H),3.80(s,3H),2.95–2.77(m,1H),2.71–2.60(m,1H),2.51(s,3H),2.39–2.20(m,1H),1.85(m,1H)。
实施例27
本实施例发现合成的硒代那可丁衍生物具有抗白血病活性，通过药理实验进行验证，具体的，使用CCK-8法开展相应的细胞增殖抑制活性分析。实验步骤如下：
1.样品配制：用DMSO(购买于Merck公司)溶解上述实施例合成的S1-S26以及那可丁(梯希爱(上海)化成工业发展有限公司)(作为阴性对照)，加入PBS配成1000mg/mL的溶液或均匀的混悬液，然后用含DMSO的PBS稀释；
2.人白血病细胞株
JURKAT、U937、KAUSMI-1(ATCC和中科院细胞库)；
3.培养液
RPMI 1640+10％FBS+双抗；
4.其他材料
全波长多功能酶标仪：Varioskan Flash型号，Thermo scientific生产厂商，进口96孔板等；
5.实验方法：本实验采用的是CCK-8法。向96孔板每个孔加入100mL浓度为7-8x 10 3个/mL的人白血病细胞株的细胞悬液，置37℃，5％CO 2培养箱内。培养24小时后，依次向每个孔中加入样品液100mL，并设三复孔。37℃，5％CO 2作用48小时。然后每个孔加入CCK-8溶液20mL，置培养箱内作用2-4小时。然后用全波长多功能酶标仪测450nm处OD值。
体外白血病细胞抑制活性结果见表1。
表1不同化合物对体外白血病细胞的活性抑制结果
Figure PCTCN2020084517-appb-000031
结果显示，与阴性对照(那可丁)相比，实施例1-26中大部分制备的硒代那可丁衍生物对白血病细胞株的细胞活性抑制效果更好，其中化合物S12的效果最好。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 一种硒代那可丁衍生物，其特征在于，所述硒代那可丁衍生物的结构通式如通式i或通式ii所示：
    Figure PCTCN2020084517-appb-100001
    所述R 1或R 2基团为烷基、环烷基、芳基、杂芳基、氧烷基、酯烷基、烯丙基、炔丙基或氰基。
  2. 根据权利要求1所述的硒代那可丁衍生物，其特征在于，所述芳基为苯基、取代苯基、联苯基、萘基或取代萘基；所述杂芳基为吡啶基、取代吡啶基、噻吩基、取代噻吩、呋喃基、取代呋喃基、吡咯基、取代吡咯基、喹啉基、取代喹啉基、异喹啉基、取代异喹啉基、苯并噻唑基、取代苯并噻唑基、吲哚基、取代吲哚基、苯并咪唑基、取代咪唑基、苯并恶唑基、取代苯并恶唑基、咪唑基、取代咪唑基、恶唑基、取代恶唑基、噻唑基或取代噻唑基；
    所述烷基为C1-C6烷基或氘代烷基；
    所述环烷基为C1-C8环烷基或氘代环烷基；
  3. 根据权利要求2所述的硒代那可丁衍生物，其特征在于，所述芳基为取代苯基。
  4. 根据权利要求1所述的硒代那可丁衍生物，其特征在于，所述硒代那可丁衍生物的结构如下式S1所示，
    Figure PCTCN2020084517-appb-100002
  5. 根据权利要求1所述的硒代那可丁衍生物，其特征在于，所述硒代那可丁衍生物的结构如下式VIII所示，
    Figure PCTCN2020084517-appb-100003
  6. 一种制备权利要求1-3任意一项所述的硒代那可丁衍生物的方法，其特征在于，包括以下步骤：
    以结构式如式I所示的化合物为底物，依次进行羟甲基化反应、氯代反应、硒氰化钾参与的亲核取代反应、硒醇原位还原生成和亲核取代反应，即得到结构通式如通式i所示的硒代那可丁衍生物；
    以结构式如式I所示的化合物为底物，依次进行溴代反应、氨基化反应、重氮化反应、硒氰化钾参与的亲核取代反应、硒醇原位还原生成和亲核取代反应，即得到结构通式如通式ii所示的硒代那可丁衍生物，或
    以结构式如式I所示的化合物为底物，直接与二硒化物进行自由基加成反应，即得到结构通式如通式ii所示的硒代那可丁衍生物；
    Figure PCTCN2020084517-appb-100004
  7. 一种制备权利要求4所述的硒代那可丁衍生物的方法，其特征在于，包括以下步骤：
    Figure PCTCN2020084517-appb-100005
  8. 一种制备权利要求5所述的硒代那可丁衍生物的方法，其特征在于，包括以下步骤：
    Figure PCTCN2020084517-appb-100006
  9. 根据权利要求1-3中任意一项所述的硒代那可丁衍生物在白血病领域中的应用。
  10. 一种治疗白血病的药物，其特征在于，所述药物的活性成分为权利要求1所述的硒代那可丁衍生物。
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