CN113880814A - 一种嘧啶胺类化合物及应用 - Google Patents
一种嘧啶胺类化合物及应用 Download PDFInfo
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- CN113880814A CN113880814A CN202010625229.XA CN202010625229A CN113880814A CN 113880814 A CN113880814 A CN 113880814A CN 202010625229 A CN202010625229 A CN 202010625229A CN 113880814 A CN113880814 A CN 113880814A
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- 238000003210 sulforhodamine B staining Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- 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)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
化合物编号 | CDK4激酶IC<sub>50</sub>(nM) | CDK6激酶IC<sub>50</sub>(nM) |
Abemaciclib | 2.6 | 18 |
BT-C-1 | <1 | <10 |
化合物编号 | 乳腺癌细胞MCF-7 | 脑胶质瘤细胞U87-MG | 脑胶质瘤细胞A172 |
Abemaciclib | 180.90 | 612.70 | 251.80 |
BT-C-1 | <50 | <10 | <10 |
BT-C-2 | <10 | <1 | <1 |
BT-C-3 | <10 | <1 | <1 |
BT-C-4 | <10 | <1 | <1 |
BT-C-8 | ND | ND | <100 |
BT-C-9 | ND | <50 | <10 |
BT-C-10 | <50 | <50 | <10 |
BT-C-11 | <1 | <10 | <10 |
BT-C-12 | <50 | <10 | <1 |
BT-C-13 | <100 | <50 | <50 |
BT-C-14 | <100 | <50 | <10 |
BT-C-17 | <10 | <1 | <1 |
化合物编号 | 小细胞肺癌细胞H69 |
Abemaciclib | 469.70 |
BT-C-1 | <10 |
BT-C-2 | <50 |
BT-C-3 | <50 |
BT-C-4 | <50 |
BT-C-8 | <200 |
BT-C-9 | <50 |
BT-C-10 | <10 |
BT-C-11 | <50 |
BT-C-12 | <10 |
BT-C-13 | <50 |
BT-C-14 | <50 |
BT-C-17 | <1 |
Claims (9)
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Cited By (1)
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CN117720518A (zh) * | 2023-12-05 | 2024-03-19 | 江苏海洋大学 | 一种苯并咪唑类化合物、其制备方法、药物组合物及应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102264725A (zh) * | 2008-12-22 | 2011-11-30 | 伊莱利利公司 | 蛋白激酶抑制剂 |
CN108602802A (zh) * | 2016-07-26 | 2018-09-28 | 深圳市塔吉瑞生物医药有限公司 | 用于抑制蛋白酪氨酸激酶活性的氨基嘧啶类化合物 |
CN108929312A (zh) * | 2017-05-22 | 2018-12-04 | 南开大学 | 具有cdk或hdac抑制活性的新型苯并杂环联嘧啶抑制剂 |
-
2020
- 2020-07-01 CN CN202010625229.XA patent/CN113880814B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102264725A (zh) * | 2008-12-22 | 2011-11-30 | 伊莱利利公司 | 蛋白激酶抑制剂 |
CN108602802A (zh) * | 2016-07-26 | 2018-09-28 | 深圳市塔吉瑞生物医药有限公司 | 用于抑制蛋白酪氨酸激酶活性的氨基嘧啶类化合物 |
CN108929312A (zh) * | 2017-05-22 | 2018-12-04 | 南开大学 | 具有cdk或hdac抑制活性的新型苯并杂环联嘧啶抑制剂 |
Non-Patent Citations (3)
Title |
---|
GIULIA STAZI ET AL.: ""Histone deacetylases as an epigenetic pillar for the development of hybrid inhibitors in cancer"", 《CURRENT OPINION IN CHEMICAL BIOLOGY》 * |
HUANG, ZHI, ET AL.: ""Novel hybrid molecule overcomes the limited response of solid tumours to HDAC inhibitors via suppressing JAK1-STAT3-BCL2 signalling"", 《THERANOSTICS 》 * |
ZHI HUANG ET AL.: ""Novel dual inhibitors targeting CDK4 and VEGFR2 synergistically suppressed cancer progression and angiogenesis"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN117720518A (zh) * | 2023-12-05 | 2024-03-19 | 江苏海洋大学 | 一种苯并咪唑类化合物、其制备方法、药物组合物及应用 |
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