CN105622658A - 非肽类蛋白酶体抑制剂、其药物组合物、制备方法和应用 - Google Patents
非肽类蛋白酶体抑制剂、其药物组合物、制备方法和应用 Download PDFInfo
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- CN105622658A CN105622658A CN201610162439.3A CN201610162439A CN105622658A CN 105622658 A CN105622658 A CN 105622658A CN 201610162439 A CN201610162439 A CN 201610162439A CN 105622658 A CN105622658 A CN 105622658A
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- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
化合物编号 | 100nM下抑制率,% | IC50(SD)a,nM |
1a | 67.65 | n.d.b |
1b | 64.79 | n.d. |
1c | 43.48 | n.d. |
1d | 47.35 | n.d. |
1e | 86.70 | 24.58(2.7) |
2a | 65.88 | n.d. |
2b | 52.30 | n.d. |
2c | 31.45 | n.d. |
2d | 42.31 | n.d. |
2e | 84.71 | 25.93(3.1) |
3a | 84.88 | 23.17(2.1) |
3b | 67.53 | n.d. |
3c | 79.81 | 44.25(4.6) |
3d | 69.19 | n.d. |
3e | 90.29 | 11.42(2.8) |
硼替佐米 | 92.50 | 4.68(0.5)c |
Claims (10)
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019086805A1 (fr) * | 2017-10-30 | 2019-05-09 | Meneses Da Silva Edna | Colorants naturels instantanes et leurs procedes de preparation |
WO2020082817A1 (zh) * | 2018-10-22 | 2020-04-30 | 普济生物科技(台州)有限公司 | 肟基萘醌类化合物及其制备方法和用途 |
CN113876784A (zh) * | 2021-09-27 | 2022-01-04 | 潍坊博创国际生物医药研究院 | 硼代亮氨酸类化合物的新用途 |
CN114075227A (zh) * | 2020-08-19 | 2022-02-22 | 北京大学 | 吡唑硼酸类化合物、包含其的药物组合物及它们的用途 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1521171A (zh) * | 2003-02-13 | 2004-08-18 | 上海雅虎制药股份有限公司 | 新型硼酸或硼酸酯类化合物、制备方法及在药学上的应用 |
CN1587255A (zh) * | 2004-07-16 | 2005-03-02 | 新乡医学院 | 萘醌类衍生物、其合成方法及其应用 |
CN103122003A (zh) * | 2011-11-17 | 2013-05-29 | 北京韩美药品有限公司 | 具有抗肿瘤活性的萘醌类化合物 |
CN103122002A (zh) * | 2011-11-17 | 2013-05-29 | 北京韩美药品有限公司 | 具有抗肿瘤活性的萘醌类化合物 |
CN103450241A (zh) * | 2008-06-17 | 2013-12-18 | 米伦纽姆医药公司 | 硼酸酯化合物及其医药组合物 |
-
2016
- 2016-03-18 CN CN201610162439.3A patent/CN105622658B/zh not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1521171A (zh) * | 2003-02-13 | 2004-08-18 | 上海雅虎制药股份有限公司 | 新型硼酸或硼酸酯类化合物、制备方法及在药学上的应用 |
CN1587255A (zh) * | 2004-07-16 | 2005-03-02 | 新乡医学院 | 萘醌类衍生物、其合成方法及其应用 |
CN103450241A (zh) * | 2008-06-17 | 2013-12-18 | 米伦纽姆医药公司 | 硼酸酯化合物及其医药组合物 |
CN103122003A (zh) * | 2011-11-17 | 2013-05-29 | 北京韩美药品有限公司 | 具有抗肿瘤活性的萘醌类化合物 |
CN103122002A (zh) * | 2011-11-17 | 2013-05-29 | 北京韩美药品有限公司 | 具有抗肿瘤活性的萘醌类化合物 |
Non-Patent Citations (5)
Title |
---|
ZACHARY MILLER ET AL.: "Proteasome Inhibitors with Pyrazole Scaffolds from Structure-Based Virtual Screening", 《J. MED. CHEM.》 * |
李磊等: "有机硼酸类酶抑制剂的研究进展", 《中国医药工业杂志》 * |
王国如等: "共价型蛋白酶体抑制剂的研究进展", 《中国新药杂志》 * |
管鹏健等: "萘醌类化合物抗肿瘤活性研究进展", 《中国药物化学杂志》 * |
贾光伟等: "蛋白酶体抑制剂的研究进展", 《精细化工中间体》 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019086805A1 (fr) * | 2017-10-30 | 2019-05-09 | Meneses Da Silva Edna | Colorants naturels instantanes et leurs procedes de preparation |
WO2020082817A1 (zh) * | 2018-10-22 | 2020-04-30 | 普济生物科技(台州)有限公司 | 肟基萘醌类化合物及其制备方法和用途 |
CN112601734A (zh) * | 2018-10-22 | 2021-04-02 | 普济生物科技(台州)有限公司 | 肟基萘醌类化合物及其制备方法和用途 |
CN112601734B (zh) * | 2018-10-22 | 2023-05-23 | 普济生物科技(台州)有限公司 | 肟基萘醌类化合物及其制备方法和用途 |
CN114075227A (zh) * | 2020-08-19 | 2022-02-22 | 北京大学 | 吡唑硼酸类化合物、包含其的药物组合物及它们的用途 |
WO2022037648A1 (zh) * | 2020-08-19 | 2022-02-24 | 北京大学 | 吡唑硼酸类化合物、包含其的药物组合物及它们的用途 |
CN114075227B (zh) * | 2020-08-19 | 2023-07-04 | 北京嵩润医药科技有限责任公司 | 吡唑硼酸类化合物、包含其的药物组合物及它们的用途 |
CN113876784A (zh) * | 2021-09-27 | 2022-01-04 | 潍坊博创国际生物医药研究院 | 硼代亮氨酸类化合物的新用途 |
CN113876784B (zh) * | 2021-09-27 | 2023-07-21 | 潍坊博创国际生物医药研究院 | 硼代亮氨酸类化合物的新用途 |
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