WO2013107278A1 - New-type anti-cancer compounds synthesized from reaction of ketone and indole derivatives - Google Patents
New-type anti-cancer compounds synthesized from reaction of ketone and indole derivatives Download PDFInfo
- Publication number
- WO2013107278A1 WO2013107278A1 PCT/CN2013/000002 CN2013000002W WO2013107278A1 WO 2013107278 A1 WO2013107278 A1 WO 2013107278A1 CN 2013000002 W CN2013000002 W CN 2013000002W WO 2013107278 A1 WO2013107278 A1 WO 2013107278A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- ring
- cancer
- aryl
- formula
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- Novel anticancer compounds synthesized by reaction of ketones with anthraquinone derivatives
- the invention relates to the reaction of ketones and terpenoids under acid catalysis to form a novel class of terpenoids, in particular to the preparation and anticancer use of such novel compounds.
- Cancer is mainly caused by chemical, physical, biological (mycotoxin, virus, etc.) and environmentally-changing carcinogenic factors. Cancer is divided into esophageal cancer, lung cancer, breast cancer, liver cancer, etc. due to different parts of the body.
- anticancer drugs such as cisplatin, vinblastine, vincristine, camptothecin and its derivatives, paclitaxel, etc., but it has no activity and little or no toxicity.
- a broad-spectrum or narrow-spectrum anticancer drug appears. Therefore, the development and exploration of a new compound with low-toxic, broad-spectrum and narrow-spectrum anticancer activity with dual efficacy and therapeutic and preventive effects has become an important research work.
- One aspect of the present invention provides a novel anticancer compound represented by the general formulae (1) and (II).
- Z is selected from the group consisting of 0, S, R ⁇ CRi;
- Z 2 is selected from the group consisting of 0, S, NR 2 , CR 2 ;
- Z 3 is selected from the group consisting of 0, S, NR 3 , CR 3 ;
- Z 4 is selected from the group consisting of 0, S, NR
- Ri, R 2 , and R 4 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, Cwo-hydrocarbyl, 2() -hydrocarbyloxy, C 2Q -hydrocarbylcarbonyl,
- the hydrocarbyl moiety can be optionally substituted with one or more halogen atoms independently selected from the group consisting of fluorine, chlorine, bromine and iodine.
- R 5 is each independently selected from the group consisting of hydrogen, d. 4 -hydrocarbyl, Cw-hydrocarbyloxy, Cw-hydrocarbylcarbonyl, Cw-hydrocarbylcarbonyloxy, phenyl ring or substituted benzene ring.
- R 7 is selected from the group consisting of hydrogen, Cn' hydrocarbyl, hydrocarbyloxy, hydrocarbylcarbonyl, _ 2 . a hydrocarbylcarbonyloxy group, an aryl group, an arylalkyl group or a -CH 2 -NR U R 12 , wherein Ru, R 12 are each independently selected from a C ⁇ -hydrocarbyl group or both are bonded to each other by 0, N or CH 2 Or a six-membered ring.
- R 9 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, nitro, -C 3 perfluoroalkyl, ⁇ -decyloxy, C 3 6 epoxyalkyl, -CH 2 -C 3 .C 6 epoxy fluorenyl, benzyloxy, saturated or unsaturated, linear or branched alkane a C 3 _C 1 () aromatic heterocyclic ring, a C 3 -C 1e heterocyclic ring-(C r C 4 ) alkylene group, wherein the heterocyclic ring contains at least one hetero atom N, 0 or 8, -NR 13 Ri4- Ri 3 and R 14 are the same or different and are selected from hydrogen, linear or branched CLC 4 fluorenyl, C 3 -C 6 cyclodecyl, dC 6 decanoyl, aryl, halogen, azide, nitro, cyanide base.
- R 10 is selected from the group consisting of hydrogen, C ⁇ o-hydrocarbyl, d.-hydrocarbylcarbonyl, aryl, and aryl.
- a t is selected from the group consisting of 0, S, S (0), S (O) 2 , and NR 1S .
- R 15 is selected from the group consisting of hydrogen, Cwo-hydrocarbyl, C l-20 -hydrocarbyl, aryl, and aryl.
- Another aspect of the present invention provides a method for producing a novel anticancer compound represented by the formula (1) and the formula (H), which is as follows:
- a compound of the formula (I) or the formula (IV) is reacted with a compound of the formula (V) in the presence of a catalyst to obtain a compound of the formula (I) or the formula ( ⁇ ).
- the catalyst in the method of preparing the compound of the formula (1), the formula (II), may be hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, sulfamic acid, silicotungstic acid, Phosphotungstic acid, phosphomolybdic acid, other Lewis acids or heteropolyacids.
- Another aspect of the invention provides a method of reacting a ketone with an anthracene derivative to form a new compound.
- the A ring may be selected from a five-membered or six-membered ring, and the five- or six-membered ring may be selected from an aromatic ring, an aromatic heterocyclic ring, a non-aromatic ring or a non-aromatic heterocyclic ring; and the B ring may be selected from an open ring and a five-membered ring.
- a ring or a six-membered ring, which may be selected from a non-aromatic ring or a non-aromatic heterocyclic ring; and R 9 , R 1 () have the same meanings as defined above.
- the compounds of formula (1), formula (II) may be prepared in crystalline or amorphous form, and if crystalline, they may optionally be solvates, for example as hydrates.
- the present invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvents, such as water.
- a compound of the formula (V) is added dropwise under reflux of an ethanol solution of the compound of the formula (III) or the formula (IV) and the catalyst.
- the ethanol solution is kept at a temperature for 3 hours after the addition, and the solvent is evaporated to obtain a mixture containing the compound of the formula (I) or (II) and other side reaction products, which are separated and purified by a silica gel column to obtain the formula (I) or ( II) Compounds.
- the compound of the formula (1) and the formula (II) of the present invention having anticancer activity can be administered to a variety of animals including mammals, particularly humans.
- the dose may be administered by a medical practitioner according to the condition of the subject, including, for example, the severity of the disease of the patient, General health, weight, age, etc. are determined.
- the biologically active pharmaceutical compounds of the present invention may be administered by various suitable routes including, for example, transdermal, transdermal and topical administration, and the like.
- the compounds represented by the formulas (1) and (II) of the present invention can be formulated into pills, tablets, capsules, and the like, and can be administered to cancer cells by oral administration through the digestive tract for the treatment of cancer and the like.
- the frequency of administration of the biologically active pharmaceutical compounds of the present invention represented by the general formulae (1), (II) can also be determined by various factors including, for example, the specific disease to be treated, the general health of the subject, and the like. Usually, 1-3 times a day for human subjects.
- the present invention provides, in another aspect, the use of a novel anticancer compound or solvate of the formula (1), (II) for the treatment or prevention of cancer or the like, comprising topically administering the compound to a patient, or to the patient's whole body The compound is administered.
- the cancer cell comprises gastric cancer, intestinal cancer, liver cancer, pancreatic cancer, esophageal cancer, chondrosarcoma, melanoma, Hodgkin's disease, leukemia, breast cancer, prostate cancer, thyroid cancer, skin cancer , bladder cancer, etc.
- the reaction liquid recovers ethanol to obtain 4-(lH-indol-3-yl)-6-fluoro-2/-benzothiopyran or 4-(1H-indol-3-yl)thiophene [2, 3-b] a mixture of 2H-thiopyran and other side reaction products.
- Purification by silica gel column chromatography to give 4-(lH-indol-3-yl)-6-fluoro-2H-benzothiopyran (a compound of formula (I) or 4-indol-3-yl) Thieno[2,3-b] 2H-thiopyran (a compound of formula (II)), yield 30-50%.
- the measured physical and chemical constants are shown in Table 1 (Compound 1 or Compound 15).
- novel anticancer compound series drugs of the present invention such as 4-(1-indol-3-yl)-6-fluoro-2H-benzothiopyran (Compound 1 of Table 1), 4-(lH- ⁇ -3- -8-fluoro-2H-benzothiopyran (Compound 2 of Table 1), 4-(1 ⁇ -indol-3-yl)-6-chloro-2H-benzothiopyran (Compound 3 of Table 1) , 4-(lH-indol-3-yl)-8-chloro-2H-benzothiopyran (Compound 4, Table 1), 4-(1-indol-3-yl)-6-methyl -2H-benzothiopyran (Compound 5 of Table 1), 4-(lH-indol-3-yl)-8-methyl-2H-benzothiopyran (Compound 6 of Table 1), 4-( lH-indodo
- Cell cancer cells were purchased from the Chinese Academy of Military Medical Sciences]
- Cell culture RPMI Medium 1640 cell culture medium, 10% (volume fraction) calf serum and 0.01% L-glutamine were formulated into culture medium. The cultured cells were routinely cultured at 37 ° C, 5% (volume fraction) CO, and saturated humidity, and the cells in the logarithmic growth phase were used for the experiments.
- MTT assay Digest the cells with 0.25% trypsin and make a single cell suspension, inoculate 96-plates at 6000-7000 cells per well, 37'C, 5% (volume fraction) C0 2 overnight, add different concentrations For the samples, the culture medium and the non-drug-treated cells were used as the blank control and the negative control, respectively, and 8 replicate wells were set in each group, and the culture was continued for 48 or 72 hours.
- Inhibition rate ( ⁇ negative control - ⁇ experimental sample) I ( ⁇ negative control - ⁇ blank control) xlOO% It can be seen from the experimental results that the new anti-cancer compound series compounds also have different degrees of inhibitory activity on cancer cells.
- the medicaments of the present invention are synthesized by using various cyclic ketones as raw materials, and various chemical reagents used in the synthesis reaction process are common and simple and easy to obtain, and the reaction yield is also ideal.
- pharmacological toxicology experiments it was shown that the series of compounds of the present invention have different degrees of inhibitory activity against cancer cells.
- the compound of the invention is widely used in the field of anticancer, and has broad research value and application prospect.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed are uses of new-type anti-cancer compounds represented by Formula (I) and Formula (II), derivatives thereof, stereoisomers thereof, racemic or non-racemic mixtures of the stereoisomers thereof or pharmaceutically acceptable salts or solvates thereof, in cancer treatment or prevention, and further disclosed are a method for preparing same and the bioactivity of same.
Description
酮类与吲哚衍生物反应合成的新型抗癌化合物 技术领域 Novel anticancer compounds synthesized by reaction of ketones with anthraquinone derivatives
本发明专利涉及酮类与吲哚类化合物在酸催化下反应，生成一类新型吲哚类 化合物， 特别涉及此类新型化合物的制备和抗癌用途。 The invention relates to the reaction of ketones and terpenoids under acid catalysis to form a novel class of terpenoids, in particular to the preparation and anticancer use of such novel compounds.
背景技术 Background technique
癌症主要是为化学的、物理的、 生物（真菌毒素、 病毒等）的和环境变化的 致癌因素所引起。 癌症因其所在身体部位不一样分为食管癌、 肺癌、 乳腺癌、 肝癌等。 目前虽然对抗癌药物进行大量研究， 市场上也有顺铂、 长春碱、 长春 新碱、 喜树碱及其衍生物、 紫杉醇等一系列抗癌活性药物， 但是还没有活性好 且毒性小或无毒的广谱或窄谱的抗癌药物出现。 因此， 开发和探求一种髙效低 毒、 具有治疗和预防双重功效的广谱和窄谱抗癌活性的新化合物， 成为当前一 项具有重要意义的研究工作。 Cancer is mainly caused by chemical, physical, biological (mycotoxin, virus, etc.) and environmentally-changing carcinogenic factors. Cancer is divided into esophageal cancer, lung cancer, breast cancer, liver cancer, etc. due to different parts of the body. At present, although a large number of anticancer drugs have been studied, there are a series of anticancer active drugs such as cisplatin, vinblastine, vincristine, camptothecin and its derivatives, paclitaxel, etc., but it has no activity and little or no toxicity. A broad-spectrum or narrow-spectrum anticancer drug appears. Therefore, the development and exploration of a new compound with low-toxic, broad-spectrum and narrow-spectrum anticancer activity with dual efficacy and therapeutic and preventive effects has become an important research work.
发明内容 Summary of the invention
本发明的一个方面在于提供一种通式 （1)、 (II)表示的新型抗癌化合物。 One aspect of the present invention provides a novel anticancer compound represented by the general formulae (1) and (II).
C e-烃基羰基氧基。 其烃基部分可以任选地被一个或多个独立地选自氟、 氯、 溴和碘的卤素原子取代。 C e-hydrocarbylcarbonyloxy. The hydrocarbyl moiety can be optionally substituted with one or more halogen atoms independently selected from the group consisting of fluorine, chlorine, bromine and iodine.
R5、 各自独立地选自氢、 d.4-烃基、 Cw-烃氧基、 Cw-烃基羰基、 Cw- 烃基羰基氧基、 苯环或取代苯环。 R 5 is each independently selected from the group consisting of hydrogen, d. 4 -hydrocarbyl, Cw-hydrocarbyloxy, Cw-hydrocarbylcarbonyl, Cw-hydrocarbylcarbonyloxy, phenyl ring or substituted benzene ring.
R7选自氢、 Cn'烃基、 烃基氧基、 烃基羰基、 _2。-烃基羰基氧 基、 芳基、 芳杂基或 -CH2-NRUR12, 其中 Ru、 R12各自独立地选自 C^-烃基或 二者由 0、 N或 CH2连成五元或六元环。 、 R9相同或不同， 各自独立地选自 氢、 卤素、 氰基、 羟基、 氨基、 硝基、 -C3全氟烃基、 ^- 垸氧基、 C3 6环 氧烷基、 -CH2-C3.C6环氧垸基、 苄氧基、 饱和或不饱和， 直链或支链 烷
基、 C3_C1()芳杂环、 C3-C1e杂环- (CrC4)亚烷基， 其中杂环至少包含一个杂原 子 N， 0或8、 -NR13Ri4-其中 Ri3、 R14相同或不同，选自氢、直链或支链 CLC4 垸基、 C3-C6环垸基、 d-C6垸酰基、 芳基、 卤素、 叠氮基、 硝基、 氰基。 其中 烷基和环垸基上的氢可以被卤素、 氰基、 羟基、 氨基、 硝基、 羧基取代。 R 7 is selected from the group consisting of hydrogen, Cn' hydrocarbyl, hydrocarbyloxy, hydrocarbylcarbonyl, _ 2 . a hydrocarbylcarbonyloxy group, an aryl group, an arylalkyl group or a -CH 2 -NR U R 12 , wherein Ru, R 12 are each independently selected from a C^-hydrocarbyl group or both are bonded to each other by 0, N or CH 2 Or a six-membered ring. And R 9 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, nitro, -C 3 perfluoroalkyl, ^-decyloxy, C 3 6 epoxyalkyl, -CH 2 -C 3 .C 6 epoxy fluorenyl, benzyloxy, saturated or unsaturated, linear or branched alkane a C 3 _C 1 () aromatic heterocyclic ring, a C 3 -C 1e heterocyclic ring-(C r C 4 ) alkylene group, wherein the heterocyclic ring contains at least one hetero atom N, 0 or 8, -NR 13 Ri4- Ri 3 and R 14 are the same or different and are selected from hydrogen, linear or branched CLC 4 fluorenyl, C 3 -C 6 cyclodecyl, dC 6 decanoyl, aryl, halogen, azide, nitro, cyanide base. The hydrogen on the alkyl group and the cycloalkyl group may be substituted by a halogen, a cyano group, a hydroxyl group, an amino group, a nitro group or a carboxyl group.
R10选自氢、 C^o-烃基、 d. -烃基羰基、 芳基、 芳杂基。 R 10 is selected from the group consisting of hydrogen, C^o-hydrocarbyl, d.-hydrocarbylcarbonyl, aryl, and aryl.
根据本发明的某些实施方案， 在通式 （1)、 式 （II )表示的抗癌化合物中， At选自 0、 S、 S ( 0)、 S (O) 2、 NR1S。 其中 R15选自氢、 Cwo-烃基、 Cl-20- 烃基幾基、 芳基、 芳杂基。 According to some embodiments of the present invention, in the anticancer compound represented by the general formula (1), the formula (II), A t is selected from the group consisting of 0, S, S (0), S (O) 2 , and NR 1S . Wherein R 15 is selected from the group consisting of hydrogen, Cwo-hydrocarbyl, C l-20 -hydrocarbyl, aryl, and aryl.
本发明的另一个方面在于提供一种制备式 （1)、 式 （H)表示的新型抗癌化 合物的方法， 步骤如下： Another aspect of the present invention provides a method for producing a novel anticancer compound represented by the formula (1) and the formula (H), which is as follows:
1 ) 式（ΠΙ )或式（IV)化合物与式（V)化合物在催化剂的存在下反应得 到式（I)或式 （Π)化合物。 1) A compound of the formula (I) or the formula (IV) is reacted with a compound of the formula (V) in the presence of a catalyst to obtain a compound of the formula (I) or the formula (Π).
根据本发明的一些实施方案， 在制备式 （1)、 式 （II)化合物的方法中， 所述 催化剂可以是盐酸、 三氟乙酸、 对甲基苯磺酸、 氨基磺酸、 硅钨酸、 磷钨酸、 磷 钼酸， 其它 Lewis酸或杂多酸。 According to some embodiments of the present invention, in the method of preparing the compound of the formula (1), the formula (II), the catalyst may be hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, sulfamic acid, silicotungstic acid, Phosphotungstic acid, phosphomolybdic acid, other Lewis acids or heteropolyacids.
本发明的另一个方面在于提供一种酮与吲哚衍生物反应生成一种新化合物的 方法。
Another aspect of the invention provides a method of reacting a ketone with an anthracene derivative to form a new compound.
其中 A环可以选自五元环或六元环， 其五元或六元环可以选自芳香环、 芳 杂环、非芳香环或非芳香杂环； B环可以选自开环、五元环或六元环， 其五元环 或六元环可以选自非芳香环或非芳香杂环； 、 R9、 R1()的定义同上所述。 Wherein the A ring may be selected from a five-membered or six-membered ring, and the five- or six-membered ring may be selected from an aromatic ring, an aromatic heterocyclic ring, a non-aromatic ring or a non-aromatic heterocyclic ring; and the B ring may be selected from an open ring and a five-membered ring. A ring or a six-membered ring, which may be selected from a non-aromatic ring or a non-aromatic heterocyclic ring; and R 9 , R 1 () have the same meanings as defined above.
在本发明的一些实施方案中， 式 （1)、 式 （II)化合物可以制备成晶形或非 晶形， 并且如果是晶体， 则其可以任选成为溶剂化物， 例如作为水合物。 本发 明在其范围内包括化学计量的溶剂化物（如水合物） 以及含有可变量溶剂 （例 如水） 的化合物。 In some embodiments of the invention, the compounds of formula (1), formula (II) may be prepared in crystalline or amorphous form, and if crystalline, they may optionally be solvates, for example as hydrates. The present invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvents, such as water.
根据本发明的一些实施方案， 在制备式 （1)、 式 （Π)化合物的方法中， 在 式 （III) 或式 （IV) 化合物和催化剂的乙醇溶液回流下滴加上式 （V)化合物 的乙醇液， 加完后保持温度反应 3h， 蒸干溶剂， 得包含式 （I)或（II)化合物 及其他副反应产物的混合物， 用硅胶色谱柱分离和纯化， 得式 （I)或 （II )化 合物。 According to some embodiments of the present invention, in the process for preparing the compound of the formula (1) or the formula (Π), a compound of the formula (V) is added dropwise under reflux of an ethanol solution of the compound of the formula (III) or the formula (IV) and the catalyst. The ethanol solution is kept at a temperature for 3 hours after the addition, and the solvent is evaporated to obtain a mixture containing the compound of the formula (I) or (II) and other side reaction products, which are separated and purified by a silica gel column to obtain the formula (I) or ( II) Compounds.
本发明的具有抗癌活性的药物通式 （1)、 式 （II)所示的化合物可施用于多 种动物， 包括哺乳动物， 特别是人。 对于需要施用本发明具有生物活性的的药 物通式 （1)、 式（Π )所示的化合物的动物或人类对象， 其剂量可由执业医师根 据该对象的情况， 包括例如患者的疾病严重情况、 一般健康状况、 体重、 年龄 等确定。 本发明的具有生物活性的药物通式（1)、 式（II)所示的化合物可通过 多种合适的途径施用， 包括例如经皮、 透皮和局部施用等。 例如， 可以将本发 明的药物通式 （1)、 （II )所示的化合物制成丸剂、 片剂、 胶囊等， 通过内服经 消化道作用于癌细胞，用于治疗癌症等。本发明的具有生物活性的药物通式（1)、 (II)所示的化合物的施用频率也可由多种因素确定，包括例如待治疗的具体疾 病、 对象的一般健康状况等。 通常， 对于人类对象每天用药 1-3次。 The compound of the formula (1) and the formula (II) of the present invention having anticancer activity can be administered to a variety of animals including mammals, particularly humans. For an animal or a human subject to which a compound of the formula (1) or formula (Π) of the present invention is to be administered, the dose may be administered by a medical practitioner according to the condition of the subject, including, for example, the severity of the disease of the patient, General health, weight, age, etc. are determined. The biologically active pharmaceutical compounds of the present invention may be administered by various suitable routes including, for example, transdermal, transdermal and topical administration, and the like. For example, the compounds represented by the formulas (1) and (II) of the present invention can be formulated into pills, tablets, capsules, and the like, and can be administered to cancer cells by oral administration through the digestive tract for the treatment of cancer and the like. The frequency of administration of the biologically active pharmaceutical compounds of the present invention represented by the general formulae (1), (II) can also be determined by various factors including, for example, the specific disease to be treated, the general health of the subject, and the like. Usually, 1-3 times a day for human subjects.
本发明在另一方面提供式（1)、（II)所示的新型抗癌化合物或溶剂化物在治 疗或预防癌症等中的用途， 包括在患者的局部施用所述化合物， 或对患者的全 身施用所述化合物。 The present invention provides, in another aspect, the use of a novel anticancer compound or solvate of the formula (1), (II) for the treatment or prevention of cancer or the like, comprising topically administering the compound to a patient, or to the patient's whole body The compound is administered.
根据本发明的一些实施方案， 所述癌细胞包括胃癌、 肠癌、 肝癌、 胰腺癌、 食道癌、 软骨肉瘤、 黑色素瘤、 霍奇金病、 白血病、 乳腺癌、 前列腺癌、 甲状 腺癌、 皮肤癌、 膀胱癌等。 According to some embodiments of the present invention, the cancer cell comprises gastric cancer, intestinal cancer, liver cancer, pancreatic cancer, esophageal cancer, chondrosarcoma, melanoma, Hodgkin's disease, leukemia, breast cancer, prostate cancer, thyroid cancer, skin cancer , bladder cancer, etc.
具体实施方式 Detailed ways
下面列举制备例和实施例对本发明加以进一步说明。这些制备例和实施例不 应理解为对本发明范围的限制。 The invention will now be further illustrated by the following examples and examples. These preparations and examples are not to be construed as limiting the scope of the invention.
制备例： 式 （1)、 (II)化合物的制备 Preparation Example: Preparation of Compounds of Formula (1), (II)
在 lmmoL 6-氟硫色满酮（一种式（I)化合物）或 lmmol 5,6-二氢 -4H噻吩
并【2，3-b】噻喃 -4-酮（一种式（II)化合物）和 ImmoL对甲苯磺酸的乙醇溶液 中， 搅拌下滴加 1.2mmoL的吲哚（一种式（V)化合物） 乙醇液， 温度控制在 80'C左右， 保持反应温度反应 3h以上。 反应液回收乙醇， 得包含 4-(lH-吲哚 -3- 基) -6-氟 -2/ -苯并硫吡喃或 4- ( 1H-吲哚 -3-基） 噻吩并【2，3-b】 2H-噻喃及其他 副反应产物的混合物。用硅胶色谱柱分离纯化得 4-(lH-吲哚 -3-基) -6-氟 -2H-苯并 硫吡喃（一种式（I)化合物）或 4- 吲哚 -3-基）噻吩并【2，3-b】 2H-噻喃（一 种式（II)化合物）， 产率 30-50%。 测得的理化常数见表 1 (化合物 1或化合物 15)。 In lmmoL 6-fluorothiochromanone (a compound of formula (I)) or 1 mmol of 5,6-dihydro-4H thiophene And [2,3-b]thiopyran-4-one (a compound of formula (II)) and ImmoL p-toluenesulfonic acid in ethanol, adding 1.2mmoL of hydrazine (a formula (V)) with stirring Compound) Ethanol solution, the temperature is controlled at about 80'C, and the reaction temperature is maintained for more than 3 hours. The reaction liquid recovers ethanol to obtain 4-(lH-indol-3-yl)-6-fluoro-2/-benzothiopyran or 4-(1H-indol-3-yl)thiophene [2, 3-b] a mixture of 2H-thiopyran and other side reaction products. Purification by silica gel column chromatography to give 4-(lH-indol-3-yl)-6-fluoro-2H-benzothiopyran (a compound of formula (I) or 4-indol-3-yl) Thieno[2,3-b] 2H-thiopyran (a compound of formula (II)), yield 30-50%. The measured physical and chemical constants are shown in Table 1 (Compound 1 or Compound 15).
表 1中的其它化合物按照类似方法采用相应的反应物制备。 The other compounds in Table 1 were prepared in a similar manner using the corresponding reactants.
化合物 2: 4-(lH-吲哚 -3-基) -8-氟 -2H-苯并硫吡喃 Compound 2: 4-(lH-indol-3-yl)-8-fluoro-2H-benzothiopyran
化合物 3: 4-(lH-吲哚 -3-基) -6-氯 -2H-苯并硫吡喃 Compound 3: 4-(lH-indol-3-yl)-6-chloro-2H-benzothiopyran
化合物 4: 4-(lH-吲哚 -3-基) -8-氯 -2H-苯并硫吡喃 Compound 4: 4-(lH-indol-3-yl)-8-chloro-2H-benzothiopyran
化合物 5: 4-(lH-吲哚 -3-基) -6-甲基 -2H-苯并硫吡喃 Compound 5: 4-(lH-indol-3-yl)-6-methyl-2H-benzothiopyran
化合物 6: 4-(lH-吲哚 -3-基) -8-甲基 -2H-苯并硫吡喃 Compound 6: 4-(lH-indol-3-yl)-8-methyl-2H-benzothiopyran
化合物 7: 4-(lH-吲哚 -3-基) -6-甲基 -7-氟 -2H-苯并硫吡喃 Compound 7: 4-(lH-indol-3-yl)-6-methyl-7-fluoro-2H-benzothiopyran
化合物 8: 4-(lH-吲哚 -3-基) -6, 8-二氯 -2H-苯并硫吡喃 Compound 8: 4-(lH-indol-3-yl)-6,8-dichloro-2H-benzothiopyran
化合物 9: 4-(lH-吲哚 -3-基) -6-甲氧基 -2H-苯并硫吡喃 Compound 9: 4-(lH-indol-3-yl)-6-methoxy-2H-benzothiopyran
化合物 10: 4-(lH-吲哚 -3-基) -8-氟 -2H-苯并吡喃 Compound 10: 4-(lH-indol-3-yl)-8-fluoro-2H-benzopyran
化合物 11 : 4-(lH-l-甲基 -吲哚 -3-基) -6-氟 -2H-苯并硫吡喃 Compound 11 : 4-(lH-l-methyl-indol-3-yl)-6-fluoro-2H-benzothiopyran
化合物 12: 4-(lH-5'-甲基 -吲哚 -3-基) -6-氟 -2H-苯并硫吡喃 Compound 12: 4-(lH-5'-methyl-indol-3-yl)-6-fluoro-2H-benzothiopyran
化合物 13: 4-(lH-吲哚- 3-基) -2H-噻喃并【2，3-b】吡啶 Compound 13: 4-(lH-吲哚-3-yl)-2H-thiopyrano[2,3-b]pyridine
化合物 14: 4-(lH-N-甲基 -吲哚 -3-基) -2H-噻喃并【2，3-b】吡啶 Compound 14: 4-(lH-N-methyl-indol-3-yl)-2H-thiopyrano[2,3-b]pyridine
化合物 15: 4- 吲哚 -3-基) 噻吩并【2,3- b】 2H-噻喃 附表 1、 部分合成化合物的理化常数 Compound 15: 4- 吲哚-3-yl) Thieno[2,3- b] 2H-thiopyran Table 1. Physical and chemical constants of partially synthesized compounds
Z00000/£10JN3/X3d 8.Ζ.01/£10ί OAV
ArH), 7.11 (dd, J = 7.8， Z00000/£10JN3/X3d 8.Ζ.01/£10ί OAV ArH), 7.11 (dd, J = 7.8,
1.2 Hz, IH , =CH-N), 1.2 Hz, IH, =CH-N),
7.04 (ddd, J = 8.1, 5.6, 7.04 (ddd, J = 8.1, 5.6,
1.0 Hz, IH, ArH), 6.90 1.0 Hz, IH, ArH), 6.90
(dd, J = 10.0, 5.8 Hz, (dd, J = 10.0, 5.8 Hz,
ΙΗ, ΑΓΗ), 6.17 (t, J = ΙΗ, ΑΓΗ), 6.17 (t, J =
5.8 Hz, IH, =CH), 3.66 5.8 Hz, IH, =CH), 3.66
- 3.26 (m, 2H, -S-CH2)) - 3.26 (m, 2H, -S-CH2))
δ 8.20 (s, 1H， NH), 7.44 δ 8.20 (s, 1H, NH), 7.44
(t, J = 7.9 Hz, 2H, (t, J = 7.9 Hz, 2H,
ArH), 7.34 (d, J = 7.9 ArH), 7.34 (d, J = 7.9
Hz, ΙΗ, ΑΓΗ), 7.25 (t, J Hz, ΙΗ, ΑΓΗ), 7.25 (t, J
= 7.6 Hz, IH ArH,), = 7.6 Hz, IH ArH,),
7.19 (d, J = 2.4 Hz, IH, 7.19 (d, J = 2.4 Hz, IH,
=CH-N), 7.12 (dd, J = 278.10 =CH-N), 7.12 (dd, J = 278.10
C18H15NS C 18 H 15 NS
11.4， 4.3 Hz, 2H,ArH), (ESI, m/z+1) 11.4, 4.3 Hz, 2H, ArH), (ESI, m/z+1)
7.01 (dd, J = 7.9, 1.1 7.01 (dd, J = 7.9, 1.1
Hz, ΙΗ, ΑΓΗ), 6.26 (t, J Hz, ΙΗ, ΑΓΗ), 6.26 (t, J
= 5.7 Hz, IH, =CH)， = 5.7 Hz, IH, =CH),
3.50 (d, J = 5.7 Hz, 2H， 3.50 (d, J = 5.7 Hz, 2H,
-S-CH2), 2.19 (s, -S-CH2), 2.19 (s,
3H,CH3). 3H, CH3).
δ 8.18 (s， ΙΗ,ΝΗ), 7.43 δ 8.18 (s, ΙΗ, ΝΗ), 7.43
(d, J = 8.2 Hz, (d, J = 8.2 Hz,
lH,ArH), 7.36 (d, J = lH,ArH), 7.36 (d, J =
8.0 Hz, lH, ArH)„ 7.25 8.0 Hz, lH, ArH) „ 7.25
- 7.20 (m, 2H, ArH), - 7.20 (m, 2H, ArH),
7.12 (d, J = 7.8 Hz, IH, 278.10 7.12 (d, J = 7.8 Hz, IH, 278.10
C18H15NS =CH-N), 7.10 - 7.06 C 18 H 15 NS =CH-N), 7.10 - 7.06
(m, 2H, ArH), 6.94 (t, J (ESI, m/z+1) (m, 2H, ArH), 6.94 (t, J (ESI, m/z+1)
CH3 = 7.6 Hz, IH ^ArH), CH 3 = 7.6 Hz, IH ^ArH),
6.23 (t, J = 5.8 Hz, IH, 6.23 (t, J = 5.8 Hz, IH,
=CH)， 3.49 (d, J = 5.8 =CH), 3.49 (d, J = 5.8
Hz, 2H, -S-CH2), 2.45 Hz, 2H, -S-CH2), 2.45
(s, 3H,CH3) (s, 3H, CH3)
8.23 (s， IH, NH), 7.46 - 7.40 (m, 2H， ArH), 7.26 8.23 (s, IH, NH), 7.46 - 7.40 (m, 2H, ArH), 7.26
- 7.24 (m, IH ,ArH), - 7.24 (m, IH, ArH),
296.09 296.09
C18H14FNS 7.23 (dd, J = 8.4， 1.5 C 18 H 14 FNS 7.23 (dd, J = 8.4, 1.5
Hz, 2H ,ArH), 7.11 (ESI, m/z+1) (ddd, J = 8.0, 7.2, 0.9 Hz, 2H, ArH), 7.11 (ESI, m/z+1) (ddd, J = 8.0, 7.2, 0.9
Hz, IH, =CH-N), 6.92 Hz, IH, =CH-N), 6.92
(d, J = 11.1 Hz, 1H，
ArH), 6.24 (t， J = 5.7 (d, J = 11.1 Hz, 1H, ArH), 6.24 (t, J = 5.7
Hz, 1H， =CH)， 3.49 (d， Hz, 1H, =CH), 3.49 (d,
J = 5.7 Hz, 2H, J = 5.7 Hz, 2H,
-S-CH2), 2.43 - 2.14 -S-CH2), 2.43 - 2.14
(m, 3H,CH3) (m, 3H, CH3)
δ 8.27 (s， 1H， NH), 7.45 δ 8.27 (s, 1H, NH), 7.45
(d, J = 8.1 Hz, 1H， (d, J = 8.1 Hz, 1H,
ArH), 7.36 (d, J = 8.1 ArH), 7.36 (d, J = 8.1
Hz, ΙΗ, ΑΓΗ), 7.29 - 7.24 (m， 2H, ArH), 7.20 Hz, ΙΗ, ΑΓΗ), 7.29 - 7.24 (m, 2H, ArH), 7.20
(d， J = 2.4 Hz, IH, 332.22 (d, J = 2.4 Hz, IH, 332.22
C17H„C12NS C 17 H„C1 2 NS
ArH), 7.17 (d, J = 2.1 (ESI, m/z+1) Hz, 1H， =CH-N), 7.15 - ArH), 7.17 (d, J = 2.1 (ESI, m/z+1) Hz, 1H, =CH-N), 7.15 -
CI CI
7.10 (m, IH, ArH), 6.27 7.10 (m, IH, ArH), 6.27
(t, J = 5.8 Hz, IH, (t, J = 5.8 Hz, IH,
=CH)， 3.53 (d, J = 5.8 =CH), 3.53 (d, J = 5.8
Hz, 2H, -S-CH2) Hz, 2H, -S-CH2)
δ 8.18 (s， 1H， NH), 7.41 δ 8.18 (s, 1H, NH), 7.41
(dd, J = 13.6, 8.2 Hz, (dd, J = 13.6, 8.2 Hz,
2H, ArH), 7.31 (d, J = 2H, ArH), 7.31 (d, J =
8.5 Hz, IH, ArH), 7.23 8.5 Hz, IH, ArH), 7.23
- 7.18 (m, 2H, ArH), - 7.18 (m, 2H, ArH),
7.09 - 7.05 (m, III), 7.09 - 7.05 (m, III),
294.09 294.09
C18H15NOS 6.84 (d, J = 2.8 Hz, IH, C 18 H 15 NOS 6.84 (d, J = 2.8 Hz, IH,
=CH-N), 6.74 (dd, J = (ESI, m/z+1) 8.5, 2.8 Hz, ΙΗ, ΑΓΗ), =CH-N), 6.74 (dd, J = (ESI, m/z+1) 8.5, 2.8 Hz, ΙΗ, ΑΓΗ),
6.27 (t, J = S.7 Hz, 1H， 6.27 (t, J = S.7 Hz, 1H,
=CH), 3.59 (s， =CH), 3.59 (s,
3H,OCH3), 3.45 (d, J = 3H, OCH3), 3.45 (d, J =
5.7 Hz, 2H， -S-CH2) 5.7 Hz, 2H, -S-CH2)
δ 8.27 (s, IH, NH), 7.54 δ 8.27 (s, IH, NH), 7.54
(d, J = 7.9 Hz, 1H， (d, J = 7.9 Hz, 1H,
ArH), 7.43 (d, J = 8.2 ArH), 7.43 (d, J = 8.2
Hz, IH, ArH), 7.28 - 7.23 (m,2H, ArH), 7.17 Hz, IH, ArH), 7.28 - 7.23 (m, 2H, ArH), 7.17
- 7.10 (m, 1H， =CH-N), 266.09 - 7.10 (m, 1H, =CH-N), 266.09
C17H12FNO 6.91 (dd, J = 9.4， 2.7 (ESI, m/z+1) C 17 H 12 FNO 6.91 (dd, J = 9.4, 2.7 (ESI, m/z+1)
Hz, IH, ArH), 6.88 - 6.82 (m，2H， ArH), 6.03 Hz, IH, ArH), 6.88 - 6.82 (m, 2H, ArH), 6.03
(t, J = 4.0 Hz, IH, (t, J = 4.0 Hz, IH,
=CH)， 4.87 (d, J = 4.0 =CH), 4.87 (d, J = 4.0
Hz, 2H)
Hz, 2H)
r00000/CT0ZN3/X3d LZLO iOZ OAV
R00000/CT0ZN3/X3d LZLO iOZ OAV
i00000/Cl0ZM3/X3d 8LZL0l/ l0Z OAV
本发明新型抗癌化合物系列药物如 4-(1 -吲哚 -3-基) -6-氟 -2H-苯并硫吡喃 (表 1化合物 1 )、 4-(lH-吲哚 -3-基) -8-氟 -2H-苯并硫吡喃（表 1化合物 2)、 4-(1Ν- 吲哚 -3-基) -6-氯 -2H-苯并硫吡喃 （表 1化合物 3)、 4-(lH-吲哚 -3-基) -8-氯 -2H-苯 并硫吡喃 （表 1化合物 4)、 4-(1 -吲哚 -3-基) -6-甲基 -2H-苯并硫吡喃 （表 1化合 物 5)、 4-(lH-吲哚 -3-基) -8-甲基 -2H-苯并硫吡喃（表 1化合物 6)、 4-(lH-吲哚 -3- 基) -6-甲基 -7-氟 -2 /-苯并硫吡喃（表 1化合物 7)、4-(lH-吲哚 -3-基) -6, 8-二氯 -2H- 苯并硫吡喃 （表 1化合物 8)、 4-(lH-吲哚 -3-基) -6-甲氧基 -2H-苯并硫吡喃 （表 1 化合物 9)、 4-(lH-吲哚 -3-基) -8-氟 -2H-苯并吡喃（表 1化合物 10)、 4-(lH-l-甲基 - 哚 -3-基) -6-氟 -2H-苯并硫吡喃 （表 1化合物 11 )、 4-(1 -5'-甲基』引噪 -3-基) -6- 氟 -2H-苯并硫吡喃（表 1化合物 12、 4-(lH-吲哚 -3-基 )- 2H-噻喃并【2，3-b】吡啶I00000/Cl0ZM3/X3d 8LZL0l/ l0Z OAV The novel anticancer compound series drugs of the present invention such as 4-(1-indol-3-yl)-6-fluoro-2H-benzothiopyran (Compound 1 of Table 1), 4-(lH-吲哚-3- -8-fluoro-2H-benzothiopyran (Compound 2 of Table 1), 4-(1Ν-indol-3-yl)-6-chloro-2H-benzothiopyran (Compound 3 of Table 1) , 4-(lH-indol-3-yl)-8-chloro-2H-benzothiopyran (Compound 4, Table 1), 4-(1-indol-3-yl)-6-methyl -2H-benzothiopyran (Compound 5 of Table 1), 4-(lH-indol-3-yl)-8-methyl-2H-benzothiopyran (Compound 6 of Table 1), 4-( lH-indol-3-yl)-6-methyl-7-fluoro-2/-benzothiopyran (Compound 7 of Table 1), 4-(lH-indol-3-yl)-6, 8 -Dichloro-2H-benzothiopyran (Compound 8 of Table 1), 4-(lH-indol-3-yl)-6-methoxy-2H-benzothiopyran (Table 1 Compound 9) 4-(lH-indol-3-yl)-8-fluoro-2H-benzopyran (Compound 10 of Table 1), 4-(lH-l-methyl-indol-3-yl)-6- Fluorin-2H-benzothiopyran (Compound 11 of Table 1), 4-(1 -5'-methyl"-noise-3-yl)-6-fluoro-2H-benzothiopyran (Table 1 compound 12, 4-(lH-indol-3-yl)-2H-thiopyrano[2,3-b]pyridine
(表 1化合物 13 )、 4-(lH小甲基 -吲哚 -3-基) - 2H-噻喃并【2，3-b】吡啶、 4- 吲哚 -3-基） 噻吩并【23-b】 2H-噻喃 （表 1化合物 15) 过对 9种癌细胞， 釆用 二倍浓度稀释法进行体外抗癌实验， 结果参见附表 2 (化合物 1~15 浓度为 lO g mL时的抑制率）。 (Table 13 compound 13), 4-(lH small methyl-indol-3-yl)-2H-thiopyrano[2,3-b]pyridine, 4-indol-3-yl)thieno[23 -b] 2H-thiopyran (Compound 15 in Table 1) In vitro anti-cancer experiments were carried out on 9 kinds of cancer cells by double dilution method. The results are shown in Appendix 2 (Compounds 1 to 15 at a concentration of 10 g mL) Inhibition rate).
供试癌细胞： Test cancer cells:
肝癌 HEPG-2、胃癌 SGC7901、肺癌细胞 A549、胃癌 BGC- 823、白血病 K562、 乳腺癌 MCF-7、 宫颈癌 Hda、 黑色素瘤 A375、 霍结肠癌 LS174T。 【癌细胞购自 中国军事医学科学院】 Liver cancer HEPG-2, gastric cancer SGC7901, lung cancer cell A549, gastric cancer BGC-823, leukemia K562, breast cancer MCF-7, cervical cancer Hda, melanoma A375, hull colon cancer LS174T. [Cell cancer cells were purchased from the Chinese Academy of Military Medical Sciences]
细胞培养： RPMI Medium 1640细胞培养基， 10% (体积分数） 小牛血清和 0.01% L-谷氨酰胺配制成培养液。培养的细胞株置于 37°C、 5% (体积分数） CO, 饱和湿度下常规培养传代， 实验均用处于对数生长期的细胞。 Cell culture: RPMI Medium 1640 cell culture medium, 10% (volume fraction) calf serum and 0.01% L-glutamine were formulated into culture medium. The cultured cells were routinely cultured at 37 ° C, 5% (volume fraction) CO, and saturated humidity, and the cells in the logarithmic growth phase were used for the experiments.
MTT实验： 用 0.25%胰酶将细胞消化并制成单细胞悬液，按每孔 6000-7000个 细胞接种于 96板， 37'C、 5% (体积分数） C02过夜,加入不同浓度的样品， 分别 以单纯的培养液和未经药物作用的细胞作为空白对照和阴性对照， 每组设 8个复 孔， 继续培养 48或 72h。 每孔加 MTT (5mg/niL ) 20μί继续培养 4h, 弃上清液， 每孔加 DMSO ^50μL t 37°C孵育 10min， 酶标仪检测 570ηπ波长处的吸光度 (Α570 ) 值。 按以下公式计算平均抑制率： MTT assay: Digest the cells with 0.25% trypsin and make a single cell suspension, inoculate 96-plates at 6000-7000 cells per well, 37'C, 5% (volume fraction) C0 2 overnight, add different concentrations For the samples, the culture medium and the non-drug-treated cells were used as the blank control and the negative control, respectively, and 8 replicate wells were set in each group, and the culture was continued for 48 or 72 hours. Each well was added with MTT (5 mg/niL) 20 μί for 4 h, the supernatant was discarded, and each well was incubated with DMSO ^50 μL t 37 ° C for 10 min, and the absorbance (Α 570 ) at 570 η π wavelength was measured by a microplate reader. Calculate the average inhibition rate as follows:
抑制率 = (Α阴性对照 -Α实验样品） I (Α阴性对照 -Α空白对照） xlOO% 从实验结果可以看出，新型抗癌化合物系列化合物对癌细胞也都有不同程度 的抑制活性。 Inhibition rate = (Α negative control - Α experimental sample) I (Α negative control - Α blank control) xlOO% It can be seen from the experimental results that the new anti-cancer compound series compounds also have different degrees of inhibitory activity on cancer cells.
总之， 本发明涉及到的药物， 都是以各种环酮作为原料合成出来的， 合成反 应过程中用到的各种化学试剂都是常见和简单易得的， 反应的收率也比较理想。 通过药理毒理学实验， 表明本发明的系列化合物对癌细胞都有不同程度的抑制 活性。 In summary, the medicaments of the present invention are synthesized by using various cyclic ketones as raw materials, and various chemical reagents used in the synthesis reaction process are common and simple and easy to obtain, and the reaction yield is also ideal. By pharmacological toxicology experiments, it was shown that the series of compounds of the present invention have different degrees of inhibitory activity against cancer cells.
本发明化合物广泛应用于抗癌领域， 有广阔的研究价值和应用前景。 The compound of the invention is widely used in the field of anticancer, and has broad research value and application prospect.
以上通过举例说明的方式描述了本发明。 但是， 应当理解， 本发明绝不仅仅 限于这些具体实施方式。 普通技术人员可以对本发明进行各种修改和改动而不 背离本发明的精神和范围。
表 2: 新7^抗癌化合物及其衍生物 (浓度为 lO g/ml)对不同癌细胞的抑制率(％) The invention has been described above by way of illustration. However, it should be understood that the present invention is by no means limited to these specific embodiments. A person skilled in the art can make various modifications and changes to the invention without departing from the spirit and scope of the invention. Table 2: Inhibition rate of new 7 ^ anticancer compounds and their derivatives (concentration of 10 g / ml) against different cancer cells (%)
15 27.78 45.56 76.11 45.23 55.36 50. 1 22.67 38.90 61.28 注： 1: 4-(lH-吲哚 -3-基) -6-氟 -2H-苯并硫吡喃 （表 1化合物 1); 2： 4-(lH- 吲噪 -3-基) -8-氟 -2H-苯并硫吡喃 （表 1化合物 2); 3： 4-(lH-吲哚 -3-基) -6-氯 -2//- 苯并硫吡喃 （表 1化合物 3); 4： 4-(1//-吲哚 -3-基) -8-氯 -2//-苯并硫吡喃 （表 1 化合物 4); 5： 4-(lH-吲哚 -3-基) -6-甲基 -2H-苯并硫吡喃（表 1化合物 5); 6: 4-(1 - 吲哚 -3-基) -8-甲基 -2H-苯并硫吡喃 （表 1化合物 6); 7: 吲哚 -3-基) -6-甲基 15 27.78 45.56 76.11 45.23 55.36 50. 1 22.67 38.90 61.28 Notes: 1: 4-(lH-indol-3-yl)-6-fluoro-2H-benzothiopyran (Compound 1 in Table 1); 2: 4 -(lH-noisy-3-yl)-8-fluoro-2H-benzothiopyran (Compound 2 of Table 1); 3: 4-(lH-indol-3-yl)-6-chloro-2 //- benzothiopyran (Compound 3 of Table 1); 4: 4-(1//-吲哚-3-yl)-8-chloro-2//-benzothiopyran (Table 1 Compound 4 5: 4-(lH-indol-3-yl)-6-methyl-2H-benzothiopyran (Compound 5 of Table 1); 6: 4-(1-indol-3-yl) -8-methyl-2H-benzothiopyran (Compound 6 of Table 1); 7: Ind-3-yl)-6-methyl
-7-氟 -2H-苯并硫吡喃 （表 1化合物 7); 8： 4-(lH-吲哚 -3-基) -6, 8-二氯 -2H-苯并 硫吡喃 （表 1化合物 8); 9： 4-(lH-吲哚 -3-基) -6-甲氧基 -2H-苯并硫吡喃 （表 1 化合物 9)； 10:4-(1H-吲哚 -3-基) -8-氟 -2H-苯并吡喃（表 1化合物 10); 11:4-(1H-1- 甲基 -吲哚 -3-基) -6-氟 -2H-苯并硫吡喃（表 1化合物 11); 12： 4-(lH-5'-甲基 -吲哚 -3-基) -6-氟 -2H-苯并硫吡喃（表 1化合物 12); 13： 4-(lH-吲哚 -3-基 )-2 /-噻喃并 【2，3-b】吡啶（表 1化合物 13): 14： 4-(lH-l-甲基-吲哚 -3-基) -2H-噻喃并【2，3-b】 吡啶（表 1化合物 14); 15： 4- (1H-吲哚 -3-基） 噻吩并【2，3-b】 2H-噻喃 （表 1 化合物 15)。
-7-fluoro-2H-benzothiopyran (Compound 7 of Table 1); 8: 4-(lH-indol-3-yl)-6, 8-dichloro-2H-benzothiopyran (Table 1 compound 8); 9: 4-(lH-indol-3-yl)-6-methoxy-2H-benzothiopyran (Table 1 Compound 9); 10:4-(1H-吲哚- 3-yl)-8-fluoro-2H-benzopyran (Compound 10 of Table 1); 11:4-(1H-1-methyl-indol-3-yl)-6-fluoro-2H-benzo Thiopyran (Compound 11 of Table 1); 12: 4-(lH-5'-methyl-indol-3-yl)-6-fluoro-2H-benzothiopyran (Compound 12 of Table 1); : 4-(lH-indol-3-yl)-2 /-thiopyrano[2,3-b]pyridine (Table 13 Compound 13): 14: 4-(lH-l-methyl-indole- 3-yl)-2H-thiopyrano[2,3-b]pyridine (Compound 14 of Table 1); 15: 4-(1H-indol-3-yl)thieno[2,3-b] 2H- Thiol (Table 1 compound 15).
Claims
1.一种通式 （1)、 （II) 表示的新型抗癌化合物、 其衍生物、 其立体异构体、 其立体异构体的外消旋或非外消旋混合物或其药学上可接受的盐或溶剂化物。 A novel anticancer compound represented by the general formulae (1), (II), a derivative thereof, a stereoisomer thereof, a racemic or non-racemic mixture of stereoisomers thereof, or a pharmaceutically acceptable compound thereof Accepted salt or solvate.
2. 根据权利要求 1 的通式 （1)、 （II) 表示的新型抗癌化合物、 其衍生物、 其立体异构体、 其立体异构体的外消旋或非外消旋混合物或其药学上可接受的 盐或溶剂化物， R5、 各自独立地选自氢、 Cw-烃基、 d.4-烃氧基、 CL4 -烃基 羰基、 -烃基羰基氧基、 苯环或取代苯环。 R7选自氢、 ^-烃基、 Cwo-烃基 氧基、 C^o-烃基羰基、 CWD-烃基羰基氧基、 芳基、 芳杂基或 -CH2-NR„R12， 其 中 R„、 R12各自独立地选自 C1-4-烃基、 d_4-烃基羰基、 C1-4-烃基羰基氧基、 苯 环或取代苯环。 、 R9相同或不同， 各自独立地选自 H、 卤素、 氰基、 羟基、 氨基、 硝基、 -C3全氟烃基、 d-C6烃基氧基、 C3.C6环氧烃基、 -CH2-C3 6环 氧烃基、苄氧基、饱和或不饱和，直链或支链 烷基、 C3.Cie芳杂环、 C3-C10 杂环- ( CrC4) 亚烷基， 其中杂环至少包含一个杂原子 N， 0或8、 -NR13R]4， 其中 R13， R14相同或不同，选自 H、直链或支链 d. i烷基、 C3-C6环垸基、 C,-C6 烷酰基、 芳基、 卤素、 叠氮基、 硝基、 氰基。 其中烷基和环烷基上的氢可以被 卤素、 氰基、 羟基、 氨基、 硝基、 羧基取代。 R1()选自氢、 Cwo-烃基、 烃 基羰基、 芳基、 杂芳基。 R1S选自氢、 Cn'烃基、 2ϋ-烃基羰基、 芳基、 杂芳 基。 2. A novel anticancer compound represented by the general formulae (1), (II) according to claim 1, a derivative thereof, a stereoisomer thereof, a racemic or non-racemic mixture of the stereoisomer thereof or A pharmaceutically acceptable salt or solvate, R 5 , each independently selected from hydrogen, Cw-hydrocarbyl, d. 4 - alkoxy, CL 4 -hydrocarbylcarbonyl, -hydrocarbylcarbonyloxy, phenyl or substituted phenyl ring . R 7 is selected from the group consisting of hydrogen, ^-hydrocarbyl, Cwo-hydrocarbyloxy, C^o-hydrocarbylcarbonyl, CWD-hydrocarbylcarbonyloxy, aryl, arylhetero or -CH 2 -NR „ R 12 , wherein R „, R 12 is independently selected from C 1-4 - hydrocarbon, d_ 4 - hydrocarbon carbonyl group, C 1-4 - hydrocarbon carbonyl group, a benzene ring or substituted benzene ring. And R 9 are the same or different and are each independently selected from the group consisting of H, halogen, cyano, hydroxy, amino, nitro, -C 3 perfluoroalkyl, dC 6 hydrocarbyloxy, C 3 .C 6 epoxy hydrocarbyl, -CH 2- C 3 6 epoxyalkyl, benzyloxy, saturated or unsaturated, linear or branched alkyl, C 3 .C ie aromatic heterocyclic, C 3 -C 10 heterocyclic - (C r C 4 ) An alkyl group, wherein the heterocyclic ring contains at least one hetero atom N, 0 or 8, -NR 13 R ]4 , wherein R 13 and R 14 are the same or different and are selected from H, a straight chain or a branched chain d. i alkyl group, C 3- C 6 cyclodecyl, C,-C 6 alkanoyl, aryl, halogen, azide, nitro, cyano. The hydrogen on the alkyl group and the cycloalkyl group may be substituted by a halogen, a cyano group, a hydroxyl group, an amino group, a nitro group or a carboxyl group. R 1 () is selected from the group consisting of hydrogen, Cwo-hydrocarbyl, hydrocarbylcarbonyl, aryl, heteroaryl. R 1S is selected from the group consisting of hydrogen, Cn' hydrocarbyl, 2 fluorene -hydrocarbylcarbonyl, aryl, heteroaryl.
3. 根据权利要求 1 的通式 （1)、 （II) 表示的新型抗癌化合物、 其衍生物、 其立体异构体、 其立体异构体的外消旋或非外消旋混合物或其药学上可接受的 盐或溶剂化物， 、 R2、 、 各自独立地选自氢、 氟、 氯、 溴、 碘、 羟基、 甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 正戊基、 异戊基、 正己基、 庚基、 辛基、 2-乙基己基、 乙烯基、 丙烯基、 丁烯基、 戊烯基、 乙炔基、 丙炔基、 丁炔基、 环丙基、 环己基、 苯基、 苄基、 萘基、 萘甲基、 甲氧基、 乙氧基、 丙 氧基、 异丙氧基、 丁氧基、 异丁氧基、 戊氧基、 己氧基、 苄氧基、 三氟甲基、 1,1,1-三氟乙基、 4-氟苯基。 上述基团中含有烃基部分时， 烃基部分可以任选地 被一个或多个独立地选自氟、 氯、 溴和碘的卤素原子取代。 、 各自独立地
选自氢、 Cw-烃基、 Cw-烃氧基、 CM-烃基羰基、 CM-烃基羰基氧基、 苯环或取 代苯环。 R7选自氢、 d.20-烃基、 d.20-烃基氧基、 d -烃基羰基、 C^-烃基羰 基氧基、 芳基、 芳杂基或 -CH2-NRUR12, 其中 Ru、 R12各自独立地选自 d.4-烃 基、 CM-烃基羰基、 Cw-烃基羰基氧基、 苯环或取代苯环。 、 R9相同或不同， 各自独立地选自 H、 卤素、 氰基、 羟基、 氨基、 硝基、 C,-C3全氟烃基、 -C6 烃基氧基、 C3_C6环氧烃基、 -CH2-C3 6环氧烃基、 苄氧基、 饱和或不饱和， 直 链或支链 CLCW垸基、 c3 :1()芳杂环、 C3-C1()杂环- (CrC4) 亚垸基， 其中杂环 至少包含一个杂原子 N， 0或8、 -NR13Ri4. 其中 R13， R14相同或不同，选自 H、 直链或支链 d. 烷基、 C3-C6环垸基、 -0；垸酰基、 芳基、 卤素、 叠氮基、 硝 基、 氰基。 其中垸基和环垸基上的氢可以被卤素、 氰基、 羟基、 氨基、 硝基、 羧基取代。 R1()选自氢、 2ϋ-烃基、 烃基羰基、 芳基、 杂芳基。 3. A novel anticancer compound represented by the general formulae (1), (II) according to claim 1, a derivative thereof, a stereoisomer thereof, a racemic or non-racemic mixture of the stereoisomer thereof or A pharmaceutically acceptable salt or solvate, R 2 , , each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, n-pentyl, isopentyl, n-hexyl, heptyl, octyl, 2-ethylhexyl, vinyl, propenyl, butenyl, pentenyl, ethynyl, propynyl, butyne , cyclopropyl, cyclohexyl, phenyl, benzyl, naphthyl, naphthylmethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxide Base, hexyloxy, benzyloxy, trifluoromethyl, 1,1,1-trifluoroethyl, 4-fluorophenyl. Where the above group contains a hydrocarbyl moiety, the hydrocarbyl moiety may be optionally substituted with one or more halogen atoms independently selected from the group consisting of fluorine, chlorine, bromine and iodine. Independently It is selected from the group consisting of hydrogen, Cw-hydrocarbyl, Cw-hydrocarbyloxy, CM-hydrocarbylcarbonyl, CM-hydrocarbylcarbonyloxy, benzene ring or substituted benzene ring. R 7 is selected from the group consisting of hydrogen, d. 20-hydrocarbyl, d. 20-hydrocarbyloxy, d-hydrocarbylcarbonyl, C^-hydrocarbylcarbonyloxy, aryl, arylhetero or -CH 2 -NR U R 12 , wherein R u and R 12 are each independently selected from the group consisting of d. 4 -hydrocarbyl, C M -hydrocarbylcarbonyl, Cw-hydrocarbylcarbonyloxy, phenyl ring or substituted benzene ring. And R 9 are the same or different and are each independently selected from the group consisting of H, halogen, cyano, hydroxy, amino, nitro, C, -C 3 perfluoroalkyl, -C 6 hydrocarbyloxy, C 3 -C 6 epoxy hydrocarbyl, -CH 2 -C 3 6 epoxyalkyl, benzyloxy, saturated or unsaturated, linear or branched CLCW fluorenyl, c 3 : 1 () aromatic heterocyclic, C 3 -C 1 () heterocyclic - ( C r C 4 ) anthracenyl, wherein the heterocyclic ring contains at least one hetero atom N, 0 or 8, -NR 13 Ri4. wherein R 13 , R 14 are the same or different and are selected from H, straight or branched d. , C 3 -C 6 cyclodecyl, -0; decanoyl, aryl, halogen, azide, nitro, cyano. The hydrogen on the sulfhydryl group and the cyclodecyl group may be substituted by a halogen, a cyano group, a hydroxyl group, an amino group, a nitro group or a carboxyl group. R 1 () is selected from the group consisting of hydrogen, 2 -hydrocarbyl, hydrocarbylcarbonyl, aryl, heteroaryl.
4. 根据权利要求 1-4的通式 （1)、 (II) 表示的新型抗癌化合物、 其衍生物、 其立体异构体、 其立体异构体的外消旋或非外消旋混合物或其药学上可接受的 盐或溶剂化物，其中所述 烃基选自 _2ΰ-焼基、 Cwo-烯基、 C2_2e-块基、 C3-20- 环烧基、 C3-2o-环; ^基、 C6-2o-芳基、 Cs-ni-芳基 -CMO-I ^基、 C3-io-环;^基 -Ci-nH^ 基、 C3_1()-环烯基 -CMO-烷基和 CM()-烧基 - C6_1(r芳基， 更优选地选自 烧基、
芳基、 C io-芳基 -Cw 院基、 C3-6-环焼基 -C 6-焼基、 C3 环稀基 -CK-院基和 Ci—6-烧基- C6-HT芳基， 更 优选地选自 -垸基、 CM-烯基、 C2_6-炔基、 C^-环垸基、 C3_6 -环烯基、 C6_8 - 芳基、 C6.1()-芳基 -C 3-垸基、 Cw-环烷基 -Cw-垸基、 C3.6-环烯基 -Cw-院基和 Cw- 垸基 - Cw。-芳基， 其所述烃基部分可以任选地被一个或多个独立地选自氟、 氯、 溴和碘的卤素原子取代。 4. A novel anticancer compound represented by the general formulae (1), (II) according to claims 1-4, a derivative thereof, a stereoisomer thereof, a racemic or non-racemic mixture of stereoisomers thereof Or a pharmaceutically acceptable salt or solvate thereof, wherein the hydrocarbon group is selected from the group consisting of ΰ 2ΰ -fluorenyl, Cwo-alkenyl, C 2 _ 2e -block, C 3 -20-cycloalkyl, C 3 -2 o - ring; ^ group, C 6 - 2 o-aryl, Cs-ni-aryl-CMO-I ^ group, C3-io- ring; ^-Ci-nH^ group, C 3 _ 1() - Cycloalkenyl-CMO-alkyl and C M() -alkyl-C 6 _ 1 (r aryl, more preferably selected from alkyl, Aryl, C io-aryl-Cw, C 3 -6-cyclodecyl-C 6-fluorenyl, C 3 ring dilute-CK-labile and Ci-6-alkyl-C6-HT More preferably selected from the group consisting of -hydrazino, CM-alkenyl, C 2 -6 -alkynyl, C^-cyclodecyl, C 3 -6 -cycloalkenyl, C 6 -8 -aryl, C 6 1 () - aryl group -C 3 - alkyl with, Cw- -Cw- embankment cycloalkyl group, C 3 6 -. -Cw- hospital cycloalkenyl group and alkyl with CW- - Cw of. An aryl group, the hydrocarbyl moiety of which may be optionally substituted by one or more halogen atoms independently selected from the group consisting of fluorine, chlorine, bromine and iodine.
5. 根据权利要求 1的通式（1)、 (II )表示的新型抗癌化合物、 其衍生物、 其 立体异构体、 其立体异构体的外消旋或非外消旋混合物或其药学上可接受的盐 或溶剂化物， 其中式 （1 )、 式 （Π) 表示的新型抗癌化合物选自- 5. The novel anticancer compound represented by the general formulae (1), (II) according to claim 1, a derivative thereof, a stereoisomer thereof, a racemic or non-racemic mixture of the stereoisomer thereof or a pharmaceutically acceptable salt or solvate wherein the novel anticancer compound represented by formula (1), formula (Π) is selected from -
4-(lH-吲哚 -3-基 -6-氟 -2H-苯并硫吡喃 4-(lH-吲哚-3-yl-6-fluoro-2H-benzothiopyran
4-(lH-吲哚 -3-基 8-氟 -2H-苯并硫吡喃 4-(lH-吲哚-3-yl 8-fluoro-2H-benzothiopyran
4-(lH-吲哚 -3-基 6-氯 -2H-苯并硫吡喃 4-(lH-吲哚-3-yl 6-chloro-2H-benzothiopyran
4-(lH-吲哚 -3-基: 8-氯 -2H-苯并硫吡喃 4-(lH-吲哚-3-yl: 8-chloro-2H-benzothiapyran
4-(li/-吲哚 -3-基 -6-甲基 -2H-苯并硫吡喃 4-(li/-吲哚-3-yl-6-methyl-2H-benzothiopyran
4-(lH-吲哚 -3-基 8-甲基 -2H-苯并硫吡喃 4-(lH-吲哚-3-yl 8-methyl-2H-benzothiopyran
4-(lH-吲哚 -3-基 6-甲基 -7-氟 -2H-苯并硫吡喃 4-(lH-indol-3-yl 6-methyl-7-fluoro-2H-benzothiopyran
4-(lH-吲哚 -3-基 -6， 8-二氯 -2H-苯并硫吡喃 4-(lH-吲哚-3-yl-6,8-dichloro-2H-benzothiopyran
4-(lH-吲哚 -3-基 6-甲氧基 -2H-苯并硫吡喃 4-(lH-吲哚-3-yl 6-methoxy-2H-benzothiopyran
4-(lH-吲哚 -3-基 8-氟 -2H-苯并吡喃 4-(lH-吲哚-3-yl 8-fluoro-2H-benzopyran
4- (1H小甲基 -吲哚 -3-基) -6-氟 -2 -苯并硫吡喃 4-(1H small methyl-indol-3-yl)-6-fluoro-2-isobenzopyran
4-(lH-5-甲基 -吲哚 -3-基) -6-氟 -2H-苯并硫吡喃
4-(1 - ^哚 -3-基) - 2H-噻喃并【2,3-b】吡啶 4-(lH-5-methyl-indol-3-yl)-6-fluoro-2H-benzothiopyran 4-(1 - ^哚-3-yl)-2H-thiopyrano[2,3-b]pyridine
4-(1 -1-甲基 -吲哚 -3-基) - 2H-噻喃并【2，3-b】吡啶 4-(1 -1-methyl-indol-3-yl)-2H-thiopyrano[2,3-b]pyridine
4- ( 1H-吲哚 -3-基） 噻吩并【2，3-b】 2H-噻喃 4-( 1H-吲哚 -3-yl) thieno[2,3-b] 2H-thiopyran
6. 一种药物组合物， 其含有根据权利要求 1-5 中任何一项的式 （1)、 (II) 表示的新型抗癌化合物、 其衍生物、 其立体异构体、 其立体异构体的外消旋或 非外消旋混合物或其药学上可接受的盐或溶剂化物、 药用辅料和任选的药用载 体。 A pharmaceutical composition comprising the novel anticancer compound represented by the formulas (1), (II) according to any one of claims 1 to 5, a derivative thereof, a stereoisomer thereof, and a stereoisomer thereof A racemic or non-racemic mixture of a pharmaceutically acceptable salt or solvate thereof, a pharmaceutically acceptable adjuvant, and optionally a pharmaceutically acceptable carrier.
7. 一种制备通式 （1)、 (II ) 表示的新型抗癌化合物、 其衍生物、 其立体异 构体、 其立体异构体的外消旋或非外消旋混合物或其药学上可接受的盐或溶剂 化物的方法， 步骤如下： 7. A novel racemic or non-racemic mixture of a novel anticancer compound represented by the general formulae (1), (II), a derivative thereof, a stereoisomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable thereof For acceptable salt or solvate methods, the steps are as follows:
式 （VI ) 化合物 (可代表式 （111 )、 式 （IV) 表示的化合物)与式 （V) 化合 物在催化剂的存在下反应得到式 （VII) (可代表式 （I) 或式 （II) 化合物）。 A compound of the formula (VI) (which may represent a compound represented by the formula (111), formula (IV)) and a compound of the formula (V) are reacted in the presence of a catalyst to give a formula (VII) (which may represent a formula (I) or a formula (II) Compound).
其中 A环可以选自五元环或六元环， 其五元或六元环可以选自芳香环、 芳 杂环、 非芳香环或非芳香杂环； 13环可以选自幵环、 五元环或六元环， -其五元环 或六元环可以选自非芳香环或非芳香杂环； Rs、 R9、 R1()的定义同权利要求 3中 所述。 Wherein the ring A may be selected from a five-membered or six-membered ring, and the five- or six-membered ring may be selected from an aromatic ring, an aromatic heterocyclic ring, a non-aromatic ring or a non-aromatic heterocyclic ring; and the 13 ring may be selected from the group consisting of an anthracene ring and a five-membered ring. A ring or a six-membered ring, - a five-membered or six-membered ring thereof may be selected from a non-aromatic ring or a non-aromatic heterocyclic ring; and Rs, R 9 , R 1 () are as defined in claim 3.
其中制备式（VII)化合物所述催化剂可以是盐酸、 三氟乙酸、 对甲基苯磺 酸、 氨基磺酸、 硅钨酸、 磷钨酸、 磷钼酸， 其它 Lewis酸或杂多酸。 The catalyst for preparing the compound of the formula (VII) may be hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, sulfamic acid, silicotungstic acid, phosphotungstic acid, phosphomolybdic acid, other Lewis acid or heteropolyacid.
8. 根据权利要求 6 的药物组合物， 其为选自软膏剂、 乳膏剂、 凝胶剂、 霜 剂、 洗剂、 栓剂、 油剂、 丸剂、 片剂、 胶囊、 注射剂和喷剂的制剂形式。 The pharmaceutical composition according to claim 6, which is in the form of a preparation selected from the group consisting of an ointment, a cream, a gel, a cream, a lotion, a suppository, an oil, a pill, a tablet, a capsule, an injection, and a spray. .
9. 根据权利要求 1 中的式 （1 )、 (Π) 表示的新型抗癌化合物、 其衍生物、 其立体异构体、 其立体异构体的外消旋或非外消旋混合物或其药学上可接受的 盐或溶剂化物用于治疗或预防癌症， 其中所述癌症包括肝癌、 胃癌、 肺癌、 白 血病、 乳腺癌、 宫颈癌、 黑色素瘤、 肠癌、 胰腺癌、 食道癌、 软骨肉瘤、 霍奇 金病、 前列腺癌、 甲状腺癌、 皮肤癌、 膀胱癌等。
9. A novel anticancer compound represented by the formula (1), (Π) according to claim 1, a derivative thereof, a stereoisomer thereof, a racemic or non-racemic mixture of the stereoisomer thereof, or A pharmaceutically acceptable salt or solvate for treating or preventing cancer, wherein the cancer includes liver cancer, gastric cancer, lung cancer, leukemia, breast cancer, cervical cancer, melanoma, intestinal cancer, pancreatic cancer, esophageal cancer, chondrosarcoma, Hodgkin's disease, prostate cancer, thyroid cancer, skin cancer, bladder cancer, etc.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100280770A CN103214470A (en) | 2012-01-18 | 2012-01-18 | Novel anticancer compound synthesized by reaction of ketone and indole derivative |
| CN201210028077.0 | 2012-01-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013107278A1 true WO2013107278A1 (en) | 2013-07-25 |
Family
ID=48798605
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2013/000002 WO2013107278A1 (en) | 2012-01-18 | 2013-01-04 | New-type anti-cancer compounds synthesized from reaction of ketone and indole derivatives |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN103214470A (en) |
| WO (1) | WO2013107278A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007047646A2 (en) * | 2005-10-14 | 2007-04-26 | Janssen Pharmaceutica, N.V. | Substituted dihydro-isoindolones useful in treating kinase disorders |
| WO2011045344A1 (en) * | 2009-10-13 | 2011-04-21 | Pierre Fabre Medicament | Pyrazolopyridine derivatives as anticancer agent |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0611814A2 (en) * | 2005-06-10 | 2008-12-09 | Bipar Sciences Inc | parp modulators and cancer treatment |
-
2012
- 2012-01-18 CN CN2012100280770A patent/CN103214470A/en active Pending
-
2013
- 2013-01-04 WO PCT/CN2013/000002 patent/WO2013107278A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007047646A2 (en) * | 2005-10-14 | 2007-04-26 | Janssen Pharmaceutica, N.V. | Substituted dihydro-isoindolones useful in treating kinase disorders |
| WO2011045344A1 (en) * | 2009-10-13 | 2011-04-21 | Pierre Fabre Medicament | Pyrazolopyridine derivatives as anticancer agent |
Non-Patent Citations (2)
| Title |
|---|
| QUEIROZ, M.J.R.P. ET AL.: "Synthesis of new heteroaryl and heteroannulated indoles from dehydrophenylalanines: antitumor evaluation", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 16, no. 10, 2008, pages 5584 - 5589, XP022673140 * |
| ZHUNGIETU, G.I. ET AL.: "Reaction of some pyrylium salts with hydrazine", KHIMIYA GETEROTSIKLICHESKIKH SOEDINENII., no. 1, 1973, pages 38 - 40 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103214470A (en) | 2013-07-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Vicini et al. | Synthesis and antiproliferative activity of benzo [d] isothiazole hydrazones | |
| US10947253B2 (en) | Fused polycyclic dimers | |
| RU2393160C2 (en) | Pharmaceutical composition containing temozolomide ester | |
| WO2023142518A1 (en) | Hydroxynaphthalenone-phenylboronic acid compound, preparation method, and use | |
| Zhu et al. | Synthesis and structure-activity relationships study of α-aminophosphonate derivatives containing a quinoline moiety | |
| US9724331B2 (en) | Use of maleimide derivatives for preventing and treating leukemia | |
| CN103222970B (en) | Asymmetric list carbonyl curcumin analog application in preparation of anti-tumor drugs | |
| WO2010099740A1 (en) | 13a-(s) desoxytylophorinine derivatives, preparation method, pharmaceutical compositon and use thereof | |
| WO2024008129A1 (en) | Compound as kat6 inhibitor | |
| KR101975299B1 (en) | Compounds containing core structure of indole acetic acid and uses thereof | |
| CN111182896A (en) | Therapeutic agent for fatty liver disease and therapeutic agent for obesity | |
| Kowah et al. | Matrine family derivatives: Synthesis, reactions procedures, mechanism, and application in medicinal, agricultural, and materials chemistry | |
| JP6854497B2 (en) | Sulfonyl amidine as an indoleamine-2,3-dioxygenase inhibitor and its production method and use | |
| CN111018686B (en) | 6-benzylidene-2-aryl ethynyl cyclohexenone derivative and preparation method and medical application thereof | |
| CN107474043A (en) | Nicotinic acid derivates and preparation method thereof and purposes | |
| CN110590778B (en) | 3, 10 di-p-methoxyphenyl 6, 12 diaza tetracubane compound, synthetic method and pharmaceutical composition | |
| WO2013107278A1 (en) | New-type anti-cancer compounds synthesized from reaction of ketone and indole derivatives | |
| CN103906751A (en) | [1,3]dioxolo[4,5-g]quinoline-6(5h)thione and [1,3]dioxolo[4,5-g][1,2,4]triazolo[1,5-a]quinoline derivatives as inhibitors of the late sv40 factor (lsf) for use in treating cancer | |
| JP2013173679A (en) | Novel chromenoindole derivative, production method of the derivative and anticancer agent including the derivative | |
| CN107501219B (en) | Asymmetric curcumin compound and application thereof in preparation of anti-gastric cancer drugs | |
| TWI419894B (en) | 4-anilinofuro[2,3-b]quinoline derivatives, their preparation processes, and pharmaceutical compositions comprising the same | |
| CN107163047B (en) | Sophoridine amine derivative and preparation method and application thereof | |
| US9758503B1 (en) | Coumarin-gossypol derivatives with antitumor activities and a method of preparing the same | |
| JP2022516922A (en) | Fluorine-containing substituted benzothiophene compounds and their pharmaceutical compositions and applications | |
| CN110526854A (en) | A kind of ɑ, alpha, beta-unsaturated ketone derivative, preparation method and the purposes as drug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13739128 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 13739128 Country of ref document: EP Kind code of ref document: A1 |