CN105001167A - 1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物及制备方法和用途 - Google Patents
1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物及制备方法和用途 Download PDFInfo
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- CN105001167A CN105001167A CN201510419210.9A CN201510419210A CN105001167A CN 105001167 A CN105001167 A CN 105001167A CN 201510419210 A CN201510419210 A CN 201510419210A CN 105001167 A CN105001167 A CN 105001167A
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- substituted
- phenyl
- amino
- quinazolyl
- compounds
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Classifications
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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PCT/CN2016/090098 WO2017008757A1 (zh) | 2015-07-16 | 2016-07-15 | 1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物及制备方法和用途 |
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CN105753793A (zh) * | 2016-01-19 | 2016-07-13 | 河北医科大学 | 芳甲酰脲偶联喹唑啉类化合物及其制备方法、药物组合物及药物用途 |
WO2017008757A1 (zh) * | 2015-07-16 | 2017-01-19 | 西安交通大学 | 1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物及制备方法和用途 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5457105A (en) * | 1992-01-20 | 1995-10-10 | Zeneca Limited | Quinazoline derivatives useful for treatment of neoplastic disease |
CN101541788A (zh) * | 2006-12-11 | 2009-09-23 | Irm责任有限公司 | 作为激酶抑制剂的化合物和组合物 |
CN103382182A (zh) * | 2013-05-17 | 2013-11-06 | 河北医科大学 | 苯基脲偶联喹唑啉类化合物及其制备方法、药物组合物及药物用途 |
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KR101434164B1 (ko) * | 2006-09-11 | 2014-08-26 | 쿠리스 인코퍼레이션 | 아연 결합 부분을 함유한 퀴나졸린 계열 egfr 억제제 |
US20080221132A1 (en) * | 2006-09-11 | 2008-09-11 | Xiong Cai | Multi-Functional Small Molecules as Anti-Proliferative Agents |
CN105001167B (zh) * | 2015-07-16 | 2018-01-05 | 西安交通大学 | 1‑取代苯基‑3‑(4‑取代苯基氨基‑6‑喹唑啉基)脲类化合物及制备方法和用途 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5457105A (en) * | 1992-01-20 | 1995-10-10 | Zeneca Limited | Quinazoline derivatives useful for treatment of neoplastic disease |
CN101541788A (zh) * | 2006-12-11 | 2009-09-23 | Irm责任有限公司 | 作为激酶抑制剂的化合物和组合物 |
CN103382182A (zh) * | 2013-05-17 | 2013-11-06 | 河北医科大学 | 苯基脲偶联喹唑啉类化合物及其制备方法、药物组合物及药物用途 |
Non-Patent Citations (1)
Title |
---|
S.MADAPA,等: "Search for new pharmacophores for antimalarial activity. Part II:Synthesis and antimalarial activity of new 6-ureido-4-anilinoquinazolines", 《BIOORGANIC&MEDICINAL CHEMISTRY》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2017008757A1 (zh) * | 2015-07-16 | 2017-01-19 | 西安交通大学 | 1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物及制备方法和用途 |
CN105753793A (zh) * | 2016-01-19 | 2016-07-13 | 河北医科大学 | 芳甲酰脲偶联喹唑啉类化合物及其制备方法、药物组合物及药物用途 |
CN105753793B (zh) * | 2016-01-19 | 2018-09-04 | 河北医科大学 | 芳甲酰脲偶联喹唑啉类化合物及其制备方法、药物组合物及药物用途 |
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