[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN102827124B - Coumarin derivatives and pharmaceutical composition thereof and purposes - Google Patents

Coumarin derivatives and pharmaceutical composition thereof and purposes Download PDF

Info

Publication number
CN102827124B
CN102827124B CN201210201758.2A CN201210201758A CN102827124B CN 102827124 B CN102827124 B CN 102827124B CN 201210201758 A CN201210201758 A CN 201210201758A CN 102827124 B CN102827124 B CN 102827124B
Authority
CN
China
Prior art keywords
methyl
chromene
oxo
carbamic acid
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201210201758.2A
Other languages
Chinese (zh)
Other versions
CN102827124A (en
Inventor
马龙
张波
李敏
薛宝玉
张碧
张炜
邱红娟
文圣焕
金孟燮
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Hanmi Pharmaceutical Co Ltd
Original Assignee
Beijing Hanmi Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Hanmi Pharmaceutical Co Ltd filed Critical Beijing Hanmi Pharmaceutical Co Ltd
Priority to CN201210201758.2A priority Critical patent/CN102827124B/en
Publication of CN102827124A publication Critical patent/CN102827124A/en
Application granted granted Critical
Publication of CN102827124B publication Critical patent/CN102827124B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to following logical coumarin derivatives shown in formula I or its pharmacologically acceptable salts or solvate; wherein, X, Y 1, Y 2, Y 3, R 1, R 2, R 3, R 4respectively as defined herein.The invention still further relates to the application of pharmaceutical composition and described compounds for treating tumor and/or the inflammation comprising above-claimed cpd.

Description

Coumarin derivatives and pharmaceutical composition thereof and purposes
Technical field
The present invention relates to a kind of coumarin derivatives, its pharmacy acceptable salt or solvate and contain their pharmaceutical composition and purposes, more particularly, the present invention relates to a kind of there is anti-tumor activity and anti-inflammatory activity coumarin derivatives, its pharmacy acceptable salt or solvate and containing their pharmaceutical composition and purposes.
Background technology
Tonka bean camphor and derivative thereof are the lactone compounds that a class is extensively present in occurring in nature, and the difference usually according to its benzo α pyrone ring substituents is divided into simply, furans, pyrans and other coumarin kind compounds 4 kinds.Coumarin kind compound has antitumor, AntiHIV1 RT activity, anti-oxidant, antibacterial, anti-arrhythmia, osteoporosis, and analgesia, relievings asthma, the multiple biological activity such as anticoagulation (non-patent literature 1,2).The antitumor action of tonka bean camphor is the focus of research always.In recent years, the antitumor action of different sources tonka bean camphor is progressively deep in molecular mechanism by various kinds of cell model research, mainly by acting on the cell cycle, cell death inducing, the propagation (non-patent literature 2) of the inhibition tumor cells such as multi-signal approach.
Simple coumarins is only at tonka bean camphor phenyl ring side C-6, C-7 or C-8 substd, and C-7 position is always for containing oxygen base.The osthole (non-patent literature 3,4) reported is to lung adenocarcinoma cell MK-1, A549, and heLa cell B16F10, liver cancer cell Bel-7402 all has obvious inhibit activities.Aesculetin (non-patent literature 5,6) is in the news by induction G1 phase cell-cycle arrest thus suppresses the propagation of leukemia cell HL-60.
Furocoumarin(e) class is that coumarins composition 7 hydroxyls and 6 or 8 bit substituents-isopentene group cyclization form furan nucleus, and degraded simultaneously loses 3 carbon atoms.The psoralene (non-patent literature 7) reported has good dose-dependent inhibition effect to breast cancer cell MCF-7, decursin, columbianadins etc. (non-patent literature 8-10) are to human gastric carcinoma cell line BGC cell, Human leukemia cell line HL-60 cell, people's epidermal carcinoma cell lines A-432 cell strain etc. has restraining effect in various degree.
Similar to furocoumarin(e), phenyl ring one is surveyed 7 hydroxyls and 6 or 8 bit substituents-isopentene group cyclization and is formed pyranoid ring, namely belongs to pyranocoumarin class.Praeruptorin C (Pra-C) in this type of is in the news and can impels leukemia HL-60 apoptosis of tumor cells (non-patent literature 11,12).
α pyrone ring there is substituent coumarins, coumarin dimer, other coumarin kind compounds such as tripolymer class also show good anti-tumor activity, as capillarin is in the news by suppressing DNA synthesis thus the propagation (non-patent literature 13) of suppression lung carcinoma cell.
The above natural coumarin kind compound group introduced of removing, the novel cpd group obtained by chemosynthesis also has and reports widely.Such as, the compound (non-patent literature 14) only on 7 of coumarin skeleton with alkoxyl group is reported; 7 and 8 at tonka bean camphor have substituting group and on 4, have methyl substituted compound (non-patent literature 15); 4 of coumarin skeleton have arylalkyl, 3 and 7 all have substituent compound (patent documentation 1); 4 of coumarin skeleton have phenyl, and there is the compound (patent documentation 2) of phenoxy group on 3; In 5,6 of coumarin skeleton, 7 has the compound (non-patent literature 16) of alkoxyl group; In 4,5,6,7 of coumarin skeleton, 8 all has substituent compound (non-patent literature 17).
Be described above the coumarin kind compound much with anti-tumor activity, but the practicality coumarins antineoplastic compound with clinical value does not also occur, so the highly active practical coumarins antineoplastic compound of research and development is significant.
Patent documentation 1: International Publication 2000/039120.
Patent documentation 2: International Publication 2004/069820.
Non-patent literature 1:Hao Guang, Wang Zhenguo, Fu Wenyan, Yang Ying.China Journal ofChinese Materia Medica, 2008,33 (18): 2016.
Non-patent literature 2:Wu longhuo, Xu ruian.Herald of Medicine, 2010,29 (4): 498.
Non-patent literature 3:Fijioka T, Furumi K, Fujii H, et al.Chem Pharm Bull, 1999,47 (1): 96.
Non-patent literature 4: Zhou Jun, Shen Xiu, Wu little Xia, etc. canceration. distortion. sudden change, 2002,14 (4): 231.
Non-patent literature 5:Chu C Y, Tsai Y Y, Wang C J, et al.Euro J Pharmacol, 2001,416 (1): 25.
Non-patent literature 6:Wang C J, Chu C Y, et al.Cancer Lett, 2002,183 (2): 163.
Non-patent literature 7:Zhao Y Y, Cai Y. China Chinese materia medica magazine, 2006,21 (6): 370.
Non-patent literature 8: Yang Xiuwei, slow wave, Wu Jun, etc. contemporary Chinese Chinese medicine, 2006,8 (10): 8.
Non-patent literature 9: Yang Xiuwei, slow wave, Ran Fuxiang, etc. contemporary Chinese Chinese medicine, 2006,8 (11): 7.
Non-patent literature 10: Yang Xiuwei, slow wave, Ran Fuxiang, etc. contemporary Chinese Chinese medicine, 2006,8 (12): 9.
Non-patent literature 11:Fong W F, Zhang J X, Wu J Y, et al.Plant Med, 2004,70 (6): 489.
Non-patent literature 12:Wu J Y, Fong W F, Zhang J X, et al.Eur J Pharmacol, 2003,473 (1): 9.
Non-patent literature 13: Jiang Youfan, Bai Bing, Shen Qingguo. Chinese medicine company, 2002,11 (8): 30.
Non-patent literature 14:Baba M, Jin Y, Mizuno A, Suzuki H, Okada Y, Takasuka N, Tokuda H, Nishino H, Okuyama T.Biol Pharm Bull.2002,25,244.
Non-patent literature 15:Mazzei M, Miele M, Nieddu E, Barbieri F, Bruzzo C, Alama A.Eur JMed Chem.2001,36,915.
Non-patent literature 16:Riveiro M E, Shaya C, Monczor F, Fernandez N, Baldi A, De Kimpe N, Rossi J, Debenedetti S, Davio C.Cancer Letters.2004,210,179.
Non-patent literature 17:Kimura S, Ito C, Jyoko N, Segawa H, Kuroda J, Okada M, Adachi S, Nakahata T, Yuasa T, Filho V C, Furukawa H, Maekawa T.Int J Cancer 2005,113,158.
Summary of the invention
The object of the present invention is to provide a kind of there is antitumor and anti-inflammatory activity novel coumarin derivative or its pharmacologically acceptable salts or solvate, comprise the pharmaceutical composition of this derivative and application thereof.
According to an aspect of the present invention, the invention provides a kind of compound of representing as following general formula (I) or its pharmacologically acceptable salts or solvate:
Wherein, X is selected from optionally by C 1-6the heteroaryl of alkyl or halogen substiuted and R 5r 6nCO-,
Y 1, Y 2and Y 3separately be selected from-N=and-CR 7=;
R 1be selected from H, halogen, C 1-6alkyl;
R 2be selected from the C be optionally optionally substituted by a hydroxyl group 1-6alkyl;
R 3and R 4, R 5, R 6separately be selected from H, OH, NH 2, C 1-6alkyl, C 1-6alkoxyl group, C 3-8cycloalkyl, C 6-10aryl, heterocyclic radical ,-COR 8,-NHCOR 8,-CONR 9r 10, wherein said heterocyclyl ground is by OH or C 1-6alkyl replaces, described C 1-6the substituting group that alkyl is optionally selected from following group replaces: halogen, OH, COOH, NH 2, C 1-6alkoxyl group, heterocyclic radical, heteroaryl ,-COOR 8,-NR 9r 10with-CONR 9r 10r 11r 12nCO-; Or
R 3and R 4combination, R 5and R 6combination, R 9and R 10combination, R 11and R 12combination can be connected nitrogen-atoms together be formed optionally by C 1-6the unit of the 4-6 at least containing at least 1 nitrogen-atoms heterocyclic radical that alkyl replaces; Or
-NR 3r 4common formation is by two (C 1-6alkyl) the amino alkylidene amino replaced;
R 5and R 6separately be selected from H, C 1-6alkyl, C 3-8cycloalkyl, C 6-10aryl; Or R 5and R 6combination be connected nitrogen-atoms together with formed at least containing 1 nitrogen-atoms 4-6 unit heterocyclic radical;
R 7be selected from H, OH, halogen, C 1-6alkyl;
Each R 8independently selected from C 1-6alkyl and heterocyclic radical;
Each R 9and R 10independently selected from H and C 1-6alkyl, or R 9and R 10combination be connected nitrogen-atoms together with formed optionally by C 1-6the unit of the 4-6 at least containing 1 nitrogen-atoms heterocyclic radical that alkyl replaces.
According to an embodiment of the invention, the present invention relates to logical formula I compound or its pharmacy acceptable salt or solvate, it is characterized in that:
X is optionally by C 1-6the pyrimidine-2-base of alkyl or halogen substiuted;
Y 1, Y 2and Y 3be separately-CR 7=;
R 1be selected from H, halogen, C 1-6alkyl;
R 2be selected from C 1-6alkyl;
R 3and R 4separately be selected from H, C 1-6alkyl ,-CONR 9r 10;
R 7be selected from H, halogen;
R 9and R 10independently selected from H and C 1-6alkyl, or R 9and R 10combination be connected nitrogen-atoms together with formed optionally by C 1-6the unit of the 4-6 at least containing 1 nitrogen-atoms heterocyclic radical that alkyl replaces.
According to an embodiment of the invention, the present invention relates to logical formula I compound or its pharmacy acceptable salt or solvate, it is characterized in that:
X is selected from R 5r 6nCO-, wherein R 5and R 6be C 1-6alkyl;
Y 1, Y 2and Y 3be separately-CR 7=;
R 1be selected from H, halogen, C 1-6alkyl;
R 2be selected from the C be optionally optionally substituted by a hydroxyl group 1-6alkyl;
R 3and R 4separately be selected from H, OH, NH 2, C 1-6alkyl, C 3-8cycloalkyl, heterocyclic radical ,-COR 8,-NHCOR 8,-CONR 9r 10, wherein said heterocyclyl ground is by OH or C 1-6alkyl replaces, described C 1-6the substituting group that alkyl is optionally selected from following group replaces: halogen, OH, COOH, NH 2, C 1-6alkoxyl group, heterocyclic radical, heteroaryl ,-COOR 8,-NR 9r 10with-CONR 9r 10; Or
R 3and R 4combination be connected nitrogen-atoms together with formed optionally by C 1-6the unit of the 4-6 at least containing at least 1 nitrogen-atoms heterocyclic radical that alkyl replaces;
R 7be selected from H, OH, halogen;
Each R 8independently selected from C 1-6alkyl and heterocyclic radical;
Each R 9and R 10independently selected from H and C 1-6alkyl, or R 9and R 10combination be connected nitrogen-atoms together with formed optionally by C 1-6the unit of the 4-6 at least containing 1 nitrogen-atoms heterocyclic radical that alkyl replaces.
According to another embodiment of the present invention, logical formula I compound is selected from one of following compound:
Dimethyl carbamic acid 2-oxo-2H-3-(3-methylaminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(N, N-Dimethylaminocarbonyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-iso-propylaminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(iso-propylaminosulfonyl) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-methylaminosulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-methylaminosulfonyl benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7 base ester,
Pyrimidine-2-base 2-oxo-2H-3-(3-methylaminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ether,
Dimethyl carbamic acid 2-oxo-2H-3-(3-methylaminosulfonyl benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(carboxymethyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(hydroxypropyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(methylaminocarbonylmethyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(ethoxycarbonylethyl group) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(hydroxyethyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(dimethylaminocarbonylmethyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(2,2,2-trifluoroethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(amino carbonyl methyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(carboxy ethyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(2,2,2-trifluoroethyl) amino-sulfonyl benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoro propyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(2,2,2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(2,2,2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(6-fluoro-3-cyclopropylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoro propyl) amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(6-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-cyclopropylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-cyclopropylamino Sulphonylbenzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoro propyl) amino-sulfonyl benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-cyclopropylamino Sulphonylbenzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 6-(2,2,2-trifluoroethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 6-(Dimethylaminoethylamino alkylsulfonyl) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(Dimethylaminoethylamino alkylsulfonyl) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (dimethyl aminoethyl) amino-sulfonyl of N, N-) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-cyclopropylamino Sulphonylbenzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoro propyl amino-sulfonyl) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(Dimethylaminoethylamino alkylsulfonyl) benzyl) the chloro-1-chromene of-4-methyl-6-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2,6-bis-fluoro-3-cyclopropylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (methylaminocarbonylmethyl) amino-sulfonyl of N, N-) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(dimethylaminocarbonylmethyl amino-sulfonyl) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (amino carbonyl methyl) amino-sulfonyl of N, N-) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2,6-bis-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(dimethylamino alkylidene amino alkylsulfonyl) benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(dimethylaminopropylamino alkylsulfonyl) benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(amino carbonyl methyl amino-sulfonyl) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(Dimethylaminoethylamino alkylsulfonyl) benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (amino carbonyl methyl) amino-sulfonyl of N, N-) benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-dimethylamino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-cyclopropylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (methylaminocarbonylmethyl) amino-sulfonyl of N, N-) benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (methylaminocarbonylmethyl) amino-sulfonyl of N, N-) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(amino carbonyl methyl amino-sulfonyl) benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (amino carbonyl methyl) amino-sulfonyl of N, N-) benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2,6-bis-fluoro-3-dimethylamino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-methyl piperidine base Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-phenylsulfamoyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-morpholinyl Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-methylaminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-methylaminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-methyl piperidine base Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-cyclopropylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-tert-butyl carbonyl diazanyl Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-propionyl diazanyl Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-chloro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
N-methyl-N ethyl-carboxylamine 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Morpholine formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Piperidine carboxylic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
N-Methyl-N-phenyl-carboxylamine 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Diisopropylaminoethyl formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the chloro-6-of 4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-7-of-4-methyl-6-(to methylpyrimidine-2-base oxygen base)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-7-of-4-methyl-6-(to ethyl-pyrimidine-2-base oxygen base)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-7-(to methylpyrimidine-2-base oxygen base)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-7-(to ethyl-pyrimidine-2-base oxygen base)-2-oxo-2H-1-chromene,
Dimethyl carbamic acid 2-oxo-2H-3-(2,4-bis-fluoro-3-aminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-diazanyl Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-hydroxyl-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-hydroxyethylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-Dimethylaminoethylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-tert-butylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-hydroxyl amino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-Dimethylaminocarbonyl amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-morpholinyl carbonylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-7-of-4-methyl-6-(to chloropyrimide-2-base oxygen base)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-7-of-4-methyl-6-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-kharophen Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-kharophen Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
3-(4-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl) the chloro-7-of-4-methyl-6-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-morpholinyl carbonylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
3-(4-fluoro-morpholinyl carbonylamino Sulphonylbenzyl) the chloro-7-of-4-methyl-6-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-methylpiperazine base carbonylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
3-(4-fluoro-morpholinyl carbonylamino Sulphonylbenzyl)-4-methyl-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl)-4-methyl-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-N-methylaminocarbonyl amino-sulfonyl benzyl) the chloro-7-of-4-methyl-6-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-N-methylaminocarbonyl amino-sulfonyl benzyl)-4-methyl-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-N-methylaminocarbonyl amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-hydroxyethyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-hydroxypropyl Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methoxy ethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methoxy-propyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(morpholinyl ethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methylpiperazinylethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(piperidinoethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-carboxymethylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-carboxyethylamino group Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(amino carbonyl methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methylaminocarbonylmethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(N, N-dimethylaminocarbonylmethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(N-methyl piperidine-4-base) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(pyridin-4-yl ethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(aminopropyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(amino-ethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(azetidine-3-base) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(pyrrolidin-3-yl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(piperidin-4-yl ethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 2-(hydroxyethylamino) Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methyl) (pyrrolidin-3-yl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(4-hydroxy cyclohexylphenyl alkyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methyl) (hydroxyethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(2,3-dihydroxypropyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methylol) (hydroxyethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(1-aminocarboxyl-2-hydroxyethylamino alkylsulfonyl) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester.
According to a further aspect in the invention, pharmaceutical composition comprises logical formula I compound or its pharmacy acceptable salt or solvate and pharmaceutically acceptable carrier.In accordance with a further aspect of the present invention, the invention provides general formula (I) compound or its pharmacy acceptable salt or solvate, it is used for the treatment of cell proliferation disorders or inflammation class disease.
According to a further aspect in the invention, the invention provides the application in the medicine manufacturing treatment cell proliferation disorders and inflammation class disease of logical formula I compound or its pharmacy acceptable salt or solvate.
Cell proliferation disorders in the present invention is the disease of the usual indication in this area, and it can be selected from tumour, is especially selected from cancer.Described cancer includes but not limited to liver cancer, cancer of the stomach, esophagus cancer, leukemia (leukemia), lung cancer, laryngocarcinoma, uterus carcinoma, intestinal cancer, mammary cancer, carcinoma of the pancreas, the cancer of the brain, neural cancer, kidney, lymphatic cancer (comprising lymphocytoma), penile cancer, ovarian cancer, cancer of anal canal, prostate cancer, colorectal carcinoma, skin carcinoma and melanoma.
In several embodiment of the present invention, described cancer is melanoma, mammary cancer, colorectal carcinoma, carcinoma of the pancreas or lung cancer.
Term definition:
" alkyl ", as group or a part for other groups, the alkyl of such as halogen substiuted, the alkyl that hydroxyl replaces or alkoxyl group can be straight chain or side chain.C 1-6alkyl represents the alkyl of 1 to 6 carbon, includes but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl; Alkoxyl group includes but not limited to methoxyl group, oxyethyl group, isopropoxy, ring propoxy-etc.
" aryl " refers to the monocycle comprising six to ten carbon atoms or the aromatic ring condensed.The example of aryl comprises phenyl and naphthyl, wherein preferred phenyl.
" heteroaryl " refers to any condensing or the aromatic ring system of non-condensed, and wherein at least one ring is selected from nitrogen containing 1-4, oxygen and sulphur heteroatomic five to octatomic ring, preferably at least one heteroatoms is selected from nitrogen.The example of heteroaryl includes but not limited to thienyl, imidazolyl, pyrazolyl, thiazolyl ， oxazolyl ， isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, benzimidazolyl-, benzopyrazoles base, indyl etc.
" cycloalkyl " refers to the saturated or part undersaturated monocycle, condensed ring or the bridged ring that comprise the carbon atom specified number.Such as C 3-8cycloalkyl refers to the cycloalkyl of three to eight carbon, comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
" heterocyclic radical " refers to the cycloalkyl defined in the present invention, the carbon atom on wherein one or more rings by oxygen, nitrogen ,-NR-, sulphur, carbonyl ,-S (O)-Huo – S (O) 2replace Deng group.Such as, heterocyclic radical can for comprising 3 to 8 ring system that 1 to 3 is selected from nitrogen, oxygen, sulphur.The example of Heterocyclylalkyl includes but not limited to morpholinyl, pyrrolidyl, piperazinyl, piperidyl, thio-morpholinyl etc.
" alkylidene amino " refers to the group with-N=C-R structure, and wherein R is alkyl defined above.
" pharmaceutically acceptable carrier " is the carrier of the inertia for pharmacy field of the usual indication in this area, auxiliary material, vehicle or thinner.It includes but not limited to: starch, lactose, sucrose, glucose, Magnesium Stearate, N.F,USP MANNITOL, Mierocrystalline cellulose, water, alcohol/water mixture, phosphate buffered saline buffer (0.01-0.1M, or more preferably 0.05M) and 0.9% salt solution, propylene glycol, polyoxyethylene glycol, vegetables oil, albumin, gelatin, washing agent (such as polysorbas20, tween 80 etc.), solubilizing agent (such as, glycerine, polyoxyethylene glycol etc.), antioxidant, sanitas, lipid acid, wax, weighting agent or tonicity modifier, for covalently bound or with the polymkeric substance of complexing of metal ion, poly(lactic acid), polyglycolic acid, hydrogel adhesive, liposome, microemulsion, multilamellar vesicle, or spheroplast agent.
" solvate ", for medicine is in crystallisation process, make the lattice of crystallization change because solvent molecule adds, the crystallization obtained is called solvate, and it includes but not limited to: hydrate, alcoholate and etherate.The solvate of above-mentioned logical formula I compound of the present invention is preferably pharmaceutically acceptable solvate, and it includes but not limited to solvate formed by second alcohol and water.
" pharmacy acceptable salt ", refers to the pharmacologically acceptable salt of general formula of the present invention (I) compound.The example of these salt comprises and mineral acid such as hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, the acid salt of phosphoric acid etc., with organic acids as formic acid, acetic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, propionic acid, citric acid, succsinic acid, tartrate, fumaric acid, butyric acid, oxalic acid, propanedioic acid, toxilic acid, lactic acid, oxysuccinic acid, carbonic acid, L-glutamic acid, the acid salt of aspartic acid etc., the salt become with mineral alkali is as received salt, sylvite etc., and with organic bases as 2-monoethanolamine, arginine, Methionin, the salt that Tutofusin tris etc. are formed.
Use and pharmaceutical composition
Usually, the compounds of this invention can form applicable formulation with one or more pharmaceutically acceptable carriers and uses.These formulations are applicable to oral administration, rectal administration, topical, and other parenteral routes are used (such as, subcutaneous, muscle, vein etc.).Such as, the formulation being applicable to oral administration comprises, capsule, tablet, granule and syrup etc.The compound of the present invention comprised in these preparations can be pressed powder or particle; Solution in water-based or non-aqueous liquid or suspension; Water-in-oil or oil-in-water emulsion etc.Above-mentioned formulation can be made up via general practice of pharmacy of active compound and one or more carriers or auxiliary material.Above-mentioned carrier needs and active compound or other auxiliary materials compatibility.For solid preparation, conventional non-toxic carrier includes but not limited to N.F,USP MANNITOL, lactose, starch, Magnesium Stearate, Mierocrystalline cellulose, glucose, sucrose etc.Carrier for liquid preparation comprises water, physiological saline, D/W, ethylene glycol and polyoxyethylene glycol etc.Active compound can form solution or suspension with above-mentioned carrier.
Concrete administering mode and formulation depend on compound itself physico-chemical property and apply the severity etc. of disease.
Composition of the present invention is prepared in the mode meeting medical practice specification, quantitative and administration.Give " significant quantity " of compound by the concrete illness that will treat, the individuality for the treatment of, the cause of illness, the factors such as the target spot of medicine and administering mode determine.Usually, generally through the dosage of parenteral administration be 1-200mg/kg.The formulation of oral administration can contain 1-1000mg/kg compound of the present invention.
The compounds of this invention representated by above-mentioned logical formula I can according to following operation, its similar operations, or other description in document operate or prepared by its similar operations.
The preparation of the compounds of this invention
Synthesis program
Logical formula I compou nd synthesis method is prepared shown in following scheme and embodiment:
Scheme one
Compound 2h in scheme one and the logical method of synthesis, describe in detail in the route map in scheme one,
1. wherein single two fluorine replaces or reacts without 3-(chlorosulfonyl) the phenylformic acid starting raw material 2a replaced and cyclopropylamine and generates sulfonamide intermediate 2b; the alkali used can select triethylamine; diisopropyl ethyl amine (DIPEA) etc.; temperature of reaction is 0 to 70 degree Celsius; reaction solvent can select tetrahydrofuran (THF) (THF); methylene dichloride (DCM) etc.; such as; between phenylformic acid SULPHURYL CHLORIDE and methylamine; take triethylamine as alkali; tetrahydrofuran (THF) is solvent, and stirring at room temperature obtains corresponding product in 3 hours.
2. sulfonamide benzoic acid intermediate 2b is reduced into corresponding alcohol 2c under the effect of reductive agent, and reductive agent can select sodium borohydride (NaBH 4)/boron trifluoride, sodium borohydride (NaBH 4)/iodine (I 2), diborane (B 2h 6) etc., reaction solvent can select tetrahydrofuran (THF), temperature of reaction be 0 degree Celsius to room temperature.
3. alcohol intermediate 2c and bromide reagent react and generate corresponding bromo compound intermediate 2d, and tetrahydrofuran (THF) selected by solvent, and brominated reagent can select phosphorus tribromide (PCl 3), sulfuric acid/hydrogen bromide (H 2sO 4/ HBr), temperature of reaction 0 degree Celsius is to room temperature, and the reaction times is 2-5 hour.
4. methyl aceto acetate is first hydrogenated sodium deprotonation under subzero 10 to 0 degrees Celsius, and be obtained by reacting intermediate 2e with bromide intermediate 2d at low temperatures subsequently, tetrahydrofuran (THF) selected by solvent.
5. intermediate 2e and substituted or unsubstituted Resorcinol react and generate coumarin kind compound intermediate 2f under strong acid dehydration conditions, temperature of reaction be subzero 10 degrees Celsius to room temperature, reaction should use the vitriol oil, and the reaction times is 4 to 15 hours.
6. intermediate 2f and N, N-dimethyl methyl acyl chlorides or other acyl chlorides reacting generating compound intermediate 2g in the basic conditions, alkali can select salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride etc., solvent can select DMF (DMF), tetrahydrofuran (THF), methylene dichloride, tetracol phenixin etc., temperature of reaction be subzero 10 degrees Celsius to room temperature, the reaction times is 1 to 5 hour.
7. intermediate 2g and halohydrocarbon react in the basic conditions and generate final product 2h, and alkali can select salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride etc., solvent can select N, dinethylformamide (DMF), tetrahydrofuran (THF) (THF), methylene dichloride (DCM), acetonitrile etc., temperature of reaction is-10 to 100 degrees Celsius, and the reaction times is 1 to 5 hour.
Scheme two
Compound 1i in scheme two and the logical method of synthesis, describe in detail in the route map in scheme two,
1. wherein starting raw material 1a generates intermediate 1b through reduction reaction, use the tetrahydrofuran solution etc. of sodium borohydride and boron trifluoride dme, temperature of reaction be 0 degree Celsius to room temperature, reaction solvent can select tetrahydrofuran (THF) (THF), and stirring at room temperature obtains corresponding product in 3 hours.
2. corresponding bromide 1c prepared by intermediate 1b and bromizating agent phosphorus tribromide, and reaction solvent can select methylene dichloride, temperature of reaction be 0 degree Celsius to room temperature.
3. methyl aceto acetate is first hydrogenated sodium deprotonation under subzero 10 to 0 degrees Celsius, and be obtained by reacting intermediate 1d with bromide intermediate 1c at low temperatures subsequently, tetrahydrofuran (THF) selected by solvent.
4. intermediate 1d and substituted or unsubstituted Resorcinol react and generate coumarin kind compound intermediate 1e under strong acid dehydration conditions, temperature of reaction be subzero 10 degrees Celsius to room temperature, reaction should use the vitriol oil, and the reaction times is 4 to 15 hours.
5. intermediate 1e and acyl chlorides or halides are reacted in the basic conditions and are generated intermediate 1f, and alkali can select salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride etc., solvent can select N, dinethylformamide (DMF), tetrahydrofuran (THF), methylene dichloride, tetracol phenixin etc., temperature of reaction be subzero 10 degrees Celsius to room temperature, the reaction times is 1 to 15 hour.
6. intermediate 1f reacts and generates intermediate 1g under ammonium chloride and zinc powder condition, and solvent can select DMF (DMF), tetrahydrofuran (THF), methyl alcohol, second alcohol and water etc., temperature of reaction is 70 degrees Celsius to 80 degrees Celsius, and the reaction times is 2 to 15 hours.
7. there is diazotization reaction in intermediate 1g under Sodium Nitrite and sour condition, intermediate 1h is generated again with the cuprous chloride acetum reaction of saturated sulfurous gas, solvent can select hydrochloric acid (HCl), acetic acid (HAc) and water etc., temperature of reaction be subzero 10 degrees Celsius to room temperature, the reaction times is 2 to 5 hours.
8. intermediate 1h reacts with amine substituent in the basic conditions and generates finalization compound 1i, alkali can select salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride etc., solvent can select DMF (DMF), tetrahydrofuran (THF), methylene dichloride etc., temperature of reaction be 0 degree Celsius to room temperature, the reaction times is 1 to 15 hour.
Embodiment
preparation embodiment
Hereafter described experiment, synthetic method and involved intermediate are illustrated of the present invention, do not limit the scope of the invention.
Test used starting raw material in the present invention or buy and prepared by known raw material from reagent suppliers or via standard method.Except as otherwise noted, the embodiment of this paper applies following condition:
1) unit of temperature is degree Celsius (DEG C); The definition of room temperature is 18-25 DEG C;
2) organic solvent uses anhydrous magnesium sulfate or anhydrous sodium sulfate drying; Rotary Evaporators is used to be spin-dried for (such as: 15mmHg, 30 DEG C) under decompression Elevated Temperature Conditions;
3) use silica gel as carrier during column chromatography for separation, TLC represents silica gel thin-layer plate;
4) under normal circumstances, the progress of reaction is by TLC or LC-MS monitoring;
5) qualification of the finished product is by nucleus magnetic resonance (Bruker AVANCE 300,300MHz) and LC-MS(Brukeresquine 6000, Agilent 1200series);
embodiment 1: dimethyl carbamic acid 2-oxo-2H-3-(3-N, N-Dimethylaminoethylamino Sulphonylbenzyl)-4- the chloro-1-chromene of methyl-6--7-base ester (title compound 2.8)synthesis
The synthesis of title compound 2.8 is according to the program preparation described in scheme one.
3-(N-cyclopropylamino alkylsulfonyl) phenylformic acid (2.2):
By cyclopropylamine (0.26g; 4.53mmol) with triethylamine (1.38g; 13.6mmol) be dissolved in tetrahydrofuran (THF) (15ml); 3-(chlorosulfonyl) phenylformic acid (1g is dripped to this solution under 0 ° of C condition; 4.53mmol, title compound 2.1) tetrahydrofuran solution (5mL).After being added dropwise to complete, be warmed up to room temperature, and stir 3h at ambient temperature.After TLC detection reaction, reaction solution is poured in the saturated aqueous common salt of 30mL, then the hydrochloric acid soln process of 1N is used to extract to PH=3. ethyl acetate (20mL × 2), organic layer saturated common salt water washing, anhydrous sodium sulfate drying, decompression desolventizing obtains shallow white solid (title compound 2.2,0.6g, 55%).
3-(methylol)-N-cyclopropyl-phenyl sulphonamide (2.3):
By sodium borohydride (0.19g; 4.97mmol) be dissolved in tetrahydrofuran (THF) (5ml); 3-(N-cyclopropylamino alkylsulfonyl) phenylformic acid (0.6g is dripped to this solution under 0 ° of C condition; 2.49mmol; title compound 2.2) tetrahydrofuran solution (5mL) and under 0 ° of C condition, stir 0.5h; then under 0 ° of C condition, boron trifluoride dimethyl ether solution (0.57g, 4.97mmol) is dripped to this solution.After being added dropwise to complete, being warmed up to room temperature and stirring at ambient temperature and spend the night.After TLC and MS detection reaction, by hydrochloric acid soln (3ml) cancellation of reaction solution 1N, extract by ethyl acetate (10mL × 2).Organic layer uses saturated common salt water washing successively, anhydrous sodium sulfate drying, removes solvent under reduced pressure and obtains colorless oil (title compound 2.3,0.4g, 71%).
3-(brooethyl)-N-cyclopropyl-phenyl sulphonamide (2.4):
3-(methylol)-N-cyclopropyl-phenyl sulphonamide (0.75g, 2.49mmol, title compound 2.3) is dissolved in tetrahydrofuran (THF) (20ml), under 0 ° of C condition, drips phosphorus tribromide (0.89g, 3.3mmol) to this solution.After being added dropwise to complete, be warmed up to room temperature, and stir 3h at ambient temperature.After TLC and MS detection reaction, reaction solution ethyl acetate (20mL × 2) extracts.Organic layer is successively with saturated sodium bicarbonate solution washing, and saturated common salt water washing, anhydrous sodium sulfate drying, decompression desolventizing obtains yellow oil (title compound 2.4,0.87g, 91%).
2-(3-cyclopropylamino Sulphonylbenzyl)-3-ethyl ketone (2.5):
Taking sodium hydride (NaH, 0.45g, 60%wt, 11.4mmol) is dissolved in 30ml tetrahydrofuran (THF), and cryosel bath is cooled to 0 ° of C.Under 0 ° of C, in this solution, instill methyl aceto acetate (1.18g, 9.10mmol), keep 0 ° of C to stir 1h.Then under 0 ° of C condition, in this solution, drip 3-(brooethyl)-N-cyclopropyl-phenyl sulphonamide (2.2g, 7.58mmol, title compound 2.4) tetrahydrofuran solution (20ml), after dropwising, be warmed up to rt while stirring overnight.After TLC and MS detection reaction, by reaction solution saturated ammonium chloride solution (10ml) cancellation, extract by ethyl acetate (30mL × 2).Organic layer uses saturated common salt water washing successively, anhydrous sodium sulfate drying, and decompression desolventizing, purification by column chromatography (normal hexane: ethyl acetate=10:1 ~ 3:1) obtains colorless oil (title compound 2.5,1.3g, 51%).
3-(3-amino-sulfonyl benzyl)-7-hydroxy-4-methyl-6-chloro-2-oxo-2H-1-chromene (2.6):
Take 2-(3-cyclopropylamino Sulphonylbenzyl)-3-ethyl ketone (0.5g; 1.47mmol, title compound 2.5) and 4-chlorine Resorcino (0.21g, 1.47mmol) be placed in tetracol phenixin (1ml); 0 ° of below C drips the vitriol oil (0.43g, 4.4mmol).After dropwising, stirring at room temperature reaction is spent the night.After TLC detection reaction, pour in frozen water and separate out white solid, suction filtration, ethyl acetate washing, dry white solid (title compound 2.6,0.5623g, 41%).
1H NMR(300Hz,DMSO)δ(ppm):11.326(s,1H),7.832(s,1H),7.637(s,2H),7.481-7.459(m,2H),7.327(s,2H),6.909(s,1H),4.01(s,2H),2.51-2.42(m,3H).
MS(ESI,m/z):[M+H] +：380.
dimethyl carbamic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester (2.7):
Take 3-(3-amino-sulfonyl benzyl)-7-hydroxy-4-methyl-6-chloro-2-oxo-2H-1-chromene (200mg; 0.53mmol; title compound 2.6) and salt of wormwood (364mg; 2.6mmol) be placed in tetrahydrofuran (THF) (10ml); in this solution, N is dripped under ice bath; N-dimethyl methyl acyl chlorides (57mg, 0.583mmol).After dropwising, return stirring spends the night.After TLC detection reaction, reaction solution poured in water (20ml), be extracted with ethyl acetate, anhydrous sodium sulfate drying, remove solvent afforded crude material under reduced pressure, recrystallization obtains white solid (title compound 2.7,0.14g, 58%).
1H NMR(300MHz,CDCl 3)δ(ppm):7.79(s,1H),7.766(s,1H),7.684(s,1H),7.27(m,1H),4.744(s,2H),4.116(s,2H),3.178(s,3H),3.052(s,3H),2.465(s,3H).
MS(ESI,m/z):[M+H] +：451
dimethyl carbamic acid 2-oxo-2H-3-(3-N, N-Dimethylaminoethylamino Sulphonylbenzyl)-4-methyl-6-chlorine -1-chromene-7-base ester (2.8):
Take dimethyl carbamic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester (50mg; 0.12mmol; title compound 2.7), N; N-dimethyl-2-chloroethyl amine (17.3mg; 0.12mmol) with salt of wormwood (50mg; 0.36mmol) be placed in acetonitrile (3ml), by the mixture room temperature for overnight of gained.After TLC detection reaction, reaction solution leached, obtain white solid (title compound 2.8,15mg, 23%) through P-HPLC purifying.
1H-NMR(300MHz,MeOH-d 4)δ:7.98(s,1H),7.81-7.74(m,2H),7.61-7.52(m,2H),7.36(s,1H),4.17(s,2H),3.32(s,3H),3.13(s,3H),3.18-3.10(m,2H),3.04(s,3H),2.91(s,6H),2.58-2.56(m,2H).
MS(ESI,m/z):[M+H] +：522.2
embodiment 2: the fluoro-3-(piperidinoethyl of dimethyl carbamic acid 2-oxo-2H-3-(4-) amino-sulfonyl benzyl)-4- the chloro-1-chromene of methyl-6--7-base ester (title compound 13)synthesis
The synthesis of title compound 13 is according to the program preparation described in scheme two.
the fluoro-3-nitrobenzyl alcohol (2) of 4-:
Sodium borohydride (22.6g, 590mmol) is dissolved in 700ml tetrahydrofuran (THF), and cryosel bath is cooled to 0 ° of C.Under 0 ° of C, in this solution, add the fluoro-3-nitrobenzoic acid of 4-(100g, 540mmol, title compound 1) in batches, keep 0 ° of C to stir 1h.In above solution, the tetrahydrofuran solution (54.2mL, 590mmol) of boron trifluoride dme is instilled again, after dropwising, in room temperature reaction 3h at 0 ° of C.TLC detection reaction, after completion of the reaction, frozen water cancellation is reacted, and is extracted with ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying.Except desolventizing obtains white solid (title compound 2,90g, 97.4%).
the fluoro-2-oil of mirbane (3) of 4-(brooethyl)-1-:
Be dissolved in 500ml methylene dichloride by fluoro-for 4-3-nitrobenzyl alcohol (50g, 290mmol, title compound 2), cryosel bath is cooled to 0 ° of C.In this solution, phosphorus tribromide (27.5mL, 290mmol) is dropwise instilled, in room temperature reaction 2h under 0 ° of C.TLC detection reaction, after completion of the reaction, frozen water cancellation is reacted, with dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying.Except desolventizing obtains yellow solid, through recrystallization purifying (normal hexane: ethyl acetate=1:1), obtain white solid (title compound 3,54g, 79.9%).
2-(3-nitro-4-luorobenzyl)-3-ethyl ketone-(5):
Taking sodium hydride (NaH, 13.8g, 345mmol) is dissolved in 400ml tetrahydrofuran (THF), and cryosel bath is cooled to 0 ° of C.Under 0 ° of C, in this solution, instill methyl aceto acetate (32.0mL, 250mmol, title compound 4), keep 0 ° of C to stir 1h.In above solution, the 100ml tetrahydrofuran solution of the fluoro-2-oil of mirbane of 4-(brooethyl)-1-(54g, 230mmol, title compound 3) is instilled again, after dropwising, in stirred overnight at room temperature at 0 ° of C.TLC detection reaction, after completion of the reaction, frozen water cancellation is reacted, and is extracted with ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying.Except the crude product of desolventizing, through purification by silica gel column chromatography (normal hexane: ethyl acetate=10:1 ~ 5:1), obtain yellow oil (title compound 5,36g, 55.4%).
the fluoro-3-nitrobenzyl of 3-(4-)-7-hydroxy-4-methyl-6-chloro-2-oxo-2H-2-chromene (7):
Take 2-(3-nitro-4-luorobenzyl)-3-ethyl ketone (36g, 127mmol, title compound 5) and 4-chlorine Resorcino (18.4g, 127mmol, title compound 6) as in cryosel bath, 0 ° of below C drips the vitriol oil (20.3ml), and after dropwising, stirring at room temperature reaction is spent the night.TLC detection reaction, after completion of the reaction, pours in frozen water, separates out white solid, suction filtration, dry, obtains white solid (title compound 7,29g, 65.9%).
dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-nitrobenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester (9):
Taking the fluoro-3-nitrobenzyl of 3-(4-)-7-hydroxy-4-methyl-6-chloro-2-oxo-2H-2-chromene (29g, 83.7mmol, title compound 7) is dissolved in 200ml tetrahydrofuran (THF) and 50ml water, and cryosel bath borehole cooling is to-10 ° of C.In this solution, add salt of wormwood (57.8g, 418.5mmol), after adding, stirring at room temperature reaction is spent the night in batches.TLC detection reaction, after completion of the reaction, pours in frozen water, separates out white solid, suction filtration, dry, obtains crude product, through recrystallization purifying (ethanol), obtains white solid (title compound 9,30g, 82.6%).
dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-aminobenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester (10):
Take dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-nitrobenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester (30g, 78.3mmol, title compound 9) be dissolved in DMF (DMF, 200ml), cryosel bath borehole cooling is to-10 ° of C.In this solution, add ammonium chloride (21.7g, 391.5mmol) and zinc powder (10.2g, 156.6mmol) respectively, after adding, heating reflux reaction spends the night.TLC detection reaction, after completion of the reaction, crosses and filters white solid.Filtrate is poured in frozen water, separate out white solid, suction filtration, dry, obtain white solid (title compound 10,40g, >100%).
dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-chlorosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester (11):
At reaction flask 1, take dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-aminobenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester (20g, 54.0mmol, title compound 10) be dissolved in 100mL hydrochloric acid and 50mL acetic acid, cryosel bath borehole cooling is to-10 ° of C.In this solution, dropwise add the aqueous solution of Sodium Nitrite (3.72g, 54.0mmol), after adding, keep-10 ° of C to stir 1h.In another three-necked bottle 2, take cuprous chloride (1.34g, 13.5mmol) and be dissolved in 100mL acetic acid, it is saturated to solution that room temperature passes into sulfur dioxide gas, reaction is cooled to 0 ° of C, the dropwise of the reaction flask 1 of cooling is joined in reaction flask 2, dropwise and continue room temperature reaction 2h.TLC detection reaction, after completion of the reaction, pours into filtrate in frozen water, and separate out yellow solid, suction filtration obtains crude product, through purification by silica gel column chromatography (methylene dichloride), obtains white solid (title compound 11,5g, 20.7%).
the fluoro-3-(piperidinoethyl of dimethyl carbamic acid 2-oxo-2H-3-(4-) amino-sulfonyl benzyl)-4-methyl-6-chlorine -1-chromene-7-base ester (13):
Take dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-chlorosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester (400mg; 0.84mmol; title compound 11) be dissolved in 10ml tetrahydrofuran (THF), in this solution, add salt of wormwood (347.8g, 2.52mmol); cryosel bath borehole cooling 0 ° of C; dropwise add 1-piperidine-1-ethanamine (126mg, 1.68mmol, title compound 12); after adding, stirring at room temperature reaction is spent the night.TLC detection reaction, after completion of the reaction, pours in frozen water, is extracted with ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, removing solvent afforded crude material, white solid (title compound 13,100mg, 20.6%) is obtained through purification by silica gel column chromatography (methylene dichloride: methyl alcohol=1:0 ~ 10:1).
1H NMR(300MHz,CDCl 3)δ(ppm):7.75-7.78(m,1H),7.69(s,1H),7.45-7.51(m,1H),7.26-7.27(m,1H),7.09-7.15(t,1H,J=8.7Hz),4.07-4.15(m,2H),3.19(s,3H),3.06(s,3H),2.98-3.02(m,2H),2.47(s,3H),2.37-2.40(m,2H),2.25(s,4H),1.50-1.57(m,4H),1.41-1.42(m,2H).
ESIMS m/z:580.3(M+H).
embodiment 3: dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-of-4-(2-hydroxyethyl)-6- chromene-7-base estersynthesis
Take dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester (468mg; 1mmol); be dissolved in tetrahydrofuran (THF) (THF, 120ml), nitrogen protection borehole cooling is to-78 ° of C.In this solution, be added dropwise to lithium hexamethyldisilazide (1mol/L, 3.2ml, 3.2mmol), after adding, keep-78 ° of below C to stir one hour.Paraformaldehyde (30mg, 1mmol) is dissolved in tetrahydrofuran (THF) (THF, 3ml), and be added drop-wise in low-temp reaction liquid, after dropwising, rise to room temperature gradually, stirring is spent the night.TLC detection reaction, after completion of the reaction, adds 20mLH in reaction solution 20, be extracted with ethyl acetate, anhydrous sodium sulfate drying.Except the crude product of desolventizing, through silica gel column chromatography, obtain white solid (56mg, 11.2%).
1H NMR(300MHz,DMSO-d 6)δ:8.08(1H,s),7.64(3H,s),7.51(2H),7.32(1H,t,J=8.4Hz),5.76(1H,s),4.92(1H,t,J=6.0Hz),4.05(2H,s),3.62(2H,q,J=Hz),3.10(5H,m),2.95(3H,s).
MS(ESI,m/z):[M+H] +：499.1
The compound prepared:
Listed by lower list one, compound utilizes similar starting raw material to prepare by being similar to method mentioned above:
table one
Numbering 018 in above-mentioned table one, 025,027,036,037, the compound of 039,044,045,053 is prepared from by scheme one, and numbering 112 compound is prepared from by scheme two and embodiment 3 method, and all the other compounds are prepared from by scheme two.
Effect example
For the test experience that the present invention relates to compound
1. growth of tumour cell Inhibition test
Materials and methods
Growth of tumour cell Inhibition test material requested of the present invention is as follows table twoshown in, cell derived is wherein CAS(Chinese Academy of Sciences Shanghai cell bank), and detect Growth of Cells by CCK-8 detection reagent (DojinDo, CK04-20).
table two
Cell is inoculated: with the cell of 0.25% trysinization logarithmic phase.Single cell suspension is made into the RPMI1640 substratum containing 10%FBS.Invitrogen Countess carries out cell counting.96 orifice plates are inoculated in by upper table Cell Name and inoculation number/hole/100uL.Blank group adds 100uL substratum.Culture plate is put in incubator, 37 DEG C, 5%CO 2overnight incubation.
Drug treating: each testing sample is from 10uM, and 5 times of dilutions, arrange 6 drug levels, each concentration does the test of multiple hole.With substratum gradient dilution testing sample, and be 2 times of final concentration.Take out Tissue Culture Plate, add the substratum containing 2 times of medicine final concentrations to be measured, 100uL/ hole.96 orifice plates are put back to incubator, 37 DEG C, 5%CO 2act on 72 hours.Control group adds the substratum of not drug containing.
Colour developing and IC 50calculating: 72 hours effect after, in incubator, take out 96 orifice plates, discard substratum in hole, add the fresh culture containing 10%CCK-8,100uL/ hole.After adding, 96 orifice plates are put back in incubator, continue to cultivate 1-4h, until present significantly orange red.450nm measures photoabsorption, makes light absorption value between 1-1.8.Cell growth rate=(administration group OD value-blank OD value)/(control group OD value-blank group OD value) × 100%.Carry out logistic matching with origin8, calculate the IC of counter sample 50value, IC 50the growth-inhibiting of lower explanation medicine to cell is more obvious.
Part of compounds in table one is for the rejection ability reference of melanoma cell A375 table three A:
the active IC of table three A 50
Compound number Active Compound number Active Compound number Active Compound number Active
001 *** 002 ** 003 *** 004 ***
005 ** 006 *** 007 * 008 **
009 * 010 *** 011 *** 012 *
013 *** 014 *** 015 ** 016 ****
017 * 018 ** 019 ** 020 *
021 * 022 ** 023 * 024 **
025 * 026 *** 027 ** 028 **
029 ** 030 ** 031 * 032 *
033 *** 034 *** 035 ** 036 **
037 ** 038 ** 039 *** 040 *
041 ** 042 ** 043 ** 044 *
045 ** 046 ** 047 ** 048 **
049 * 054 * 051 *** 052 ***
053 *** 058 * 055 ** 056 ***
057 ** 062 ** 059 * 060 ***
061 ** 066 *** 063 *** 064 **
065 *** 070 ** 071 ** 068 **
069 ** 074 * 075 * 072 *
073 * 078 * 079 * 076 *
077 * 082 *** 083 ** 080 *
081 * 090 *** 091 *** 084 *
085 ** 112 ** 099 ** 092 ***
093 ** 106 ** 099 ** 104 **
* IC is represented 50>1 μM
* represents IC 50=0.1 μM ~ 1 μM
* * represents IC 50=0.01 μM ~ 0.1 μM
* * * represents IC 50<0.01 μM
Above-mentioned vitro detection experimental data shows, formula of the present invention (I) above-claimed cpd has the activity suppressing A375 growth of tumour cell, the activity that some compounds display is wherein very strong.
Part of compounds in table one is for the rejection ability reference of colon cancer cell Colo-205 table three B:
the active IC of table three B 50
Compound number Active Compound number Active Compound number Active Compound number Active
114 * 115 ** 116 * 117 *
118 * 119 ** 122 ** 123 *
124 * 125 ** 126 * 127 **
128 ** 129 ** 130 ** 131 *
132 ** 133 ** 134 ** 135 **
136 ** 137 ** 138 **
* IC is represented 50>1 μM
* represents IC 50=0.1 μM ~ 1 μM
Above-mentioned vitro detection experimental data shows, formula of the present invention (I) above-claimed cpd has the activity suppressing Colo-205 growth of tumour cell.
Rejection ability (the reference of compound of the present invention to kinds of tumor cells is detected for the part of compounds in table one table four):
table four: active IC 50
* IC is represented 50>1 μM
* represents IC 50=0.1 μM ~ 1 μM
* * represents IC 50=0.01 μM ~ 0.1 μM
Above-mentioned vitro detection experimental data shows, the kinds of tumor cells growth in formula of the present invention (I) representation compound his-and-hers watches four has restraining effect.
Compound of the present invention is tested for Normocellular rejection ability (reference for the part of compounds in table one table five):
table five
Above-mentioned vitro detection experimental data shows, formula of the present invention (I) representation compound without obvious restraining effect, has good security to normal cell Hs27.
2. stability study method (the mensuration side of Compound ira vitro metabolic stability of compound of the present invention in hepatomicrosome method)
Compound dissolution of the present invention to be measured, in acetonitrile or acetonitrile-water (1/1, V/V), makes the storing solution that concentration is 1mM.2 μ l storing solutions add in centrifuge tube, then 148 μ l phosphoric acid buffer (50mM are added, pH 7.4) and 10 μ l hepatomicrosomes (protein concentration is 20mg/ml) suspension, in 37 DEG C of water-baths, incubate 3 minutes in advance after mixing, then add 40 μ l NADPH and system occurs (containing NADP +: 6.5mM, G-6-P ester: 16.5mM, MgCl 2: 16.5mM, G-6-P ester desaturase: 2U/ml) start reaction, add 400 μ l acetonitrile termination reactions hatch 0.5 hour in 37 DEG C of water-baths after, mediation concussion 3 minutes, centrifugal (13000rpm) 5 minutes, gets supernatant liquor HPLC and detects residual drug concentration C r.
0 minute response sample of parallel preparation: mixed system adds 400 μ l acetonitriles after incubating taking-up in 3 minutes in advance in 37 DEG C, then adds 40 μ l NADPH and systems occur.Mediation concussion, after 3 minutes, centrifugal 5 minutes, gets supernatant liquor HPLC detection of drugs concentration C 0.
The residue per-cent of medicine in incubation system calculates according to the following formula:
Medicine residue (%)=C r÷ C 0× 100%
Hepatomicrosome stability (with reference to table six) for the part of compounds test the compounds of this invention in table one:
table six
Table six test experience data show, formula of the present invention (I) representation compound is more stable under hepatomicrosome environment.
3. the pharmacokinetics research of compound in rat body
After male SD rat is bought in, raise 7 days in this laboratory adaptability.8 SD rats are divided into 2 groups at random, often organize 4, and one group is used for gastric infusion, and another group is used for tail vein injection administration.The rat of gastric infusion group, needs overnight fast before administration.After rat administration, adopt the method for orbital venous plexus blood sampling at following time point blood sample collection: 0min (before administration), 5min, 15min, 30min, 1h, 2h, 3h, 5h, 7.5h, 24h.Each blood sampling time point blood sampling volume is about 300ul.The blood sample gathered with the centrifugal 5min of the rotating speed of 12000rpm at 4 ° of C, then gathers upper plasma sample, and preserves to be measured in-20 ° of C refrigerators.Experimental implementation is summed up and is seen the following form seven:
table seven
Use the compound concentration in the LC-MS/MS detection blood plasma in this laboratory.The pharmacokinetics professional software WinNonlin in this laboratory is used to calculate pharmacokinetic parameter.
Carried out bioavailability study for compound in table one 053, the bioavailability measuring this compound is as stated above 98%, shows that this compound has good oral administration biaavailability.
4. animal tumor Cell suppression test
Dilute after de-for the digestion of the cell (source is in table two) of monolayer culture wall for certain density cell suspension, transplant trunk on the right side of nude mice with 1ml syringe subcutaneous.Treat that gross tumor volume grows to 500-600mm 3after, after knurl is taken out, cutting, selecting well-grown and without degeneration necrosis, in talking tumor tissue that is red, flesh of fish shape, be cut into small pieces (about 5 × 5 × 5mm); Outside nude mice back part of animal, cut off-individual osculum, with 12G inoculating needle, knurl block is sent in otch subcutaneous.Knurl block can be used for the pharmacodynamic evaluation of antitumor drug after passing 2-3 generation.Treat that tumor-bearing mice gross tumor volume grows to 100-150mm 3, good for tumor growth animal is carried out random packet, and starts administration, dosage regimen sees the following form eight.After grouping, the pendulous frequency of diameter of tumor is determined according to the growing state of transplanted tumor, is generally 2-3 time weekly, and each measurement also needs to claim mouse heavy simultaneously.Gross tumor volume calculation formula is: TV(mm 3)=major diameter (a) × minor axis (b) 2/ 2.Generally terminate experiment after 24 to 48 hours in last administration, and calculate each group of inhibition rate of tumor growth, calculation formula is TGI=(TV ctrl-TV tre)/TV ctrl× 100%.
table eight
Nude mice quantity Measure medicine Dosage Administration volume Route of administration Dosage period
8 053 100mg/kg 10ul/g p.o. Bidx14
For compound in table one 053, carried out the research of animal tumor Cell suppression test, the TGI measured by the method for above-mentioned table eight is: A375,77%; MDA-MB-231,65.6%; Bx-PC-3,75%, have no obvious the weight of animals in experiment and reduce phenomenon, show that this compound has good anti-tumor in vivo drug effect, possess good security simultaneously.
5. extracorporeal anti-inflammatory activity experiment
1. experiment material
1.1. clone
RAW264.7 (mouse macrophage; ATCC No.TIB-71) be purchased from Beijing consonance medical university
1.2. substratum
DMEM(Gibco#11995) 10% foetal calf serum (FBS, Gibco#) is added
1.3. reagent
LPS (Sigma, #L6529-1MG); Mouse TNF-α ELISA kit (DKW12-2720-096)
1.4. equipment
Cell counter (invitrogen, C10227); Microplate reader (Tecan IF200)
2. experimental technique
2.1. cell inoculation
With 3 × 10 5the density inoculation RAW264.7 cell in individual/100 μ l/ holes, in 96 orifice plates, is cultivated about 6 hours for 37 DEG C.
2.2. medical preconditioning: final concentration, from 50 μMs, with cell culture medium 5 times of gradient dilutions, arranges 6 concentration point, duplicate hole, pre-treatment 2 hours.
2.3.LPS stimulate: add the LPS that final concentration is 30ng/ml, irritation cell about 16 hours.
2.4.TNF-α detects
After LPS stimulates 16 hours, the centrifugal 10min of 3,000rpm collects nutrient solution supernatant and dilution about 100 times, with mouse; TNF-α ELISA kit detects TNF-alpha levels.
2.5. interpretation of result
Excel 2007，OriginPro 8.0.
3.ELISA uses
3.1. before using, all reagent is fully mixed, avoid producing foam.
3.2. experimentally hole (blank and standard substance) quantity, determines required lath number.Sample (containing standard substance) and blank all should do multiple hole.
3.3. application of sample: 100ul/ hole adds the TNF-α standard substance after dilution to standard sample wells, and 100ul/ hole adds sample to sample well, arranges blank well.
3.4. add detection antibody: 50ul/ hole adds the biotinylated antibody after dilution.After mixing, cover shrouding film, 37 DEG C of incubation 90min.
3.5. plate is washed: button removes liquid in hole, and 300ul/ hole adds 1 × lavation buffer solution; Liquid in hole is discarded after stopping 1min.Repeat 4 times, filter paper is buckled dry.
3.6. enzyme-added: 100ul/ hole adds the Streptavidin-HRP after dilution.Cover shrouding film, 37 DEG C of incubation 30min.
3.7. plate is washed: button removes liquid in hole, and 300ul/ hole adds 1 × lavation buffer solution; Liquid in hole is discarded after stopping 1min.Repeat 4 times, filter paper is buckled dry.
3.8. develop the color: 100ul/ hole adds TMB, and 37 DEG C of Incubation in dark 20min, add stop buffer, measure 450nm light absorption value in 10 minutes.
4. reference
Funakoshi,T.,et al.(2012)A novel NF-kappaB inhibitor,dehydroxymethylepoxyquinomicin,ameliorates inflammatory colonic injury in mice,JCrohns Colitis,6,215-225.
Sae-Wong,C.,et al.(2011)Suppressive effects of methoxyflavonoids isolated fromKaempferia parviflora on inducible nitric oxide synthase(iNOS)expression in RAW 264.7cells,J Ethnopharmacol,136,488-495.
Sun,B.W.,et al.(2010)[Inhibitive effect of exogenous carbon monoxide-releasingmolecules 2 on the activation of Janus kinase/signal transducer and activator of transcriptionpathway in sepsis],Zhonghua Shao Shang Za Zhi,26,100-103.
Yu,T.,et al.(2012)The ability of an ethanol extract of Cinnamomum cassia to inhibitSrc and spleen tyrosine kinase activity contributes to its anti-inflammatory action,JEthnopharmacol,139,566-573.
For compound in table one 053, carry out the research of the active Inhibition test of above-mentioned extracorporeal anti-inflammatory, its EC 50for: 86nM, shows that this compound has good extracorporeal anti-inflammatory active.
The change that those skilled in the art do when should recognize the scope and spirit of the present invention disclosed in the claim do not departed from appended by the present invention and retouching, within the protection domain all belonging to claim of the present invention.

Claims (8)

1. the compound represented by following logical formula I and pharmacologically acceptable salts thereof:
Wherein, X is selected from optionally by C 1-6the heteroaryl of alkyl or halogen substiuted and R 5r 6nCO-;
Y 1, Y 2and Y 3separately be selected from-N=and-CR 7=;
R 1be selected from H, halogen, C 1-6alkyl;
R 2be selected from the C be optionally optionally substituted by a hydroxyl group 1-6alkyl;
R 3and R 4separately be selected from H, OH, NH 2, C 1-6alkyl, C 3-8cycloalkyl, C 6-10aryl, heterocyclic radical ,-COR 8,-NHCOR 8,-CONR 9r 10, wherein said heterocyclyl ground is by OH or C 1-6alkyl replaces, described C 1-6the substituting group that alkyl is optionally selected from following group replaces: halogen, OH, COOH, NH 2, C 1-6alkoxyl group, heterocyclic radical, heteroaryl ,-COOR 8,-NR 9r 10with-CONR 9r 10; Or
R 3and R 4combination be connected nitrogen-atoms together with formed optionally by C 1-6the unit of the 4-6 at least containing 1 nitrogen-atoms heterocyclic radical that alkyl replaces; Or
-NR 3r 4common formation is by two (C 1-6alkyl) the amino alkylidene amino replaced;
R 5and R 6separately be selected from H, C 1-6alkyl, C 3-8cycloalkyl, C 6-10aryl; Or R 5and R 6combination be connected nitrogen-atoms together with formed at least containing 1 nitrogen-atoms 4-6 unit heterocyclic radical;
R 7be selected from H, OH, halogen, C 1-6alkyl;
Each R 8independently selected from C 1-6alkyl and heterocyclic radical;
Each R 9and R 10independently selected from H and C 1-6alkyl, or R 9and R 10combination be connected nitrogen-atoms together with formed optionally by C 1-6the unit of the 4-6 at least containing 1 nitrogen-atoms heterocyclic radical that alkyl replaces.
2. compound as claimed in claim 1 or its pharmacy acceptable salt, is characterized in that:
X is optionally by C 1-6the pyrimidine-2-base of alkyl or halogen substiuted;
Y 1, Y 2and Y 3be separately-CR 7=;
R 1be selected from H, halogen, C 1-6alkyl;
R 2be selected from C 1-6alkyl;
R 3and R 4separately be selected from H, C 1-6alkyl ,-CONR 9r 10;
R 7be selected from H, halogen;
R 9and R 10independently selected from H and C 1-6alkyl, or R 9and R 10combination be connected nitrogen-atoms together with formed optionally by C 1-6the unit of the 4-6 at least containing 1 nitrogen-atoms heterocyclic radical that alkyl replaces.
3. compound as claimed in claim 1 or its pharmacy acceptable salt, is characterized in that:
X is selected from R 5r 6nCO-, wherein R 5and R 6be C 1-6alkyl;
Y 1, Y 2and Y 3be separately-CR 7=;
R 1be selected from H, halogen, C 1-6alkyl;
R 2be selected from the C be optionally optionally substituted by a hydroxyl group 1-6alkyl;
R 3and R 4separately be selected from H, OH, NH 2, C 1-6alkyl, C 3-8cycloalkyl, heterocyclic radical ,-COR 8,-NHCOR 8,-CONR 9r 10, wherein said heterocyclyl ground is by OH or C 1-6alkyl replaces, described C 1-6the substituting group that alkyl is optionally selected from following group replaces: halogen, OH, COOH, NH 2, C 1-6alkoxyl group, heterocyclic radical, heteroaryl ,-COOR 8,-NR 9r 10with-CONR 9r 10; Or
R 3and R 4combination be connected nitrogen-atoms together with formed optionally by C 1-6the unit of the 4-6 at least containing at least 1 nitrogen-atoms heterocyclic radical that alkyl replaces;
R 7be selected from H, OH, halogen;
Each R 8independently selected from C 1-6alkyl and heterocyclic radical;
Each R 9and R 10independently selected from H and C 1-6alkyl, or R 9and R 10combination be connected nitrogen-atoms together with formed optionally by C 1-6the unit of the 4-6 at least containing 1 nitrogen-atoms heterocyclic radical that alkyl replaces.
4. compound as claimed in claim 1 or its pharmacy acceptable salt, is characterized in that, described compound is selected from one of following:
Dimethyl carbamic acid 2-oxo-2H-3-(3-methylaminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(N, N-Dimethylaminocarbonyl) (methyl) amino-sulfonyl) the chloro-1-chromene of benzyl-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-iso-propylaminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(iso-propylaminosulfonyl) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-methylaminosulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-methylaminosulfonyl benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7 base ester,
Pyrimidine-2-base 2-oxo-2H-3-(3-methylaminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ether,
Dimethyl carbamic acid 2-oxo-2H-3-(3-methylaminosulfonyl benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(carboxymethyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(hydroxypropyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(methylaminocarbonylmethyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(ethoxycarbonylethyl group) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(hydroxyethyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(dimethylaminocarbonylmethyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(2,2,2-trifluoroethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(amino carbonyl methyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(carboxy ethyl) (methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(2,2,2-trifluoroethyl) amino-sulfonyl benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoro propyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(2,2,2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(2,2,2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(6-fluoro-3-cyclopropylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoro propyl) amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(6-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-cyclopropylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-cyclopropylamino Sulphonylbenzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoro propyl) amino-sulfonyl benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-cyclopropylamino Sulphonylbenzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 6-(2,2,2-trifluoroethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 6-(Dimethylaminoethylamino alkylsulfonyl) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(N-Dimethylaminoethylamino alkylsulfonyl) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (dimethyl aminoethyl) amino-sulfonyl of N, N-) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-cyclopropylamino Sulphonylbenzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(3,3,3-trifluoro propyl amino-sulfonyl) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(Dimethylaminoethylamino alkylsulfonyl) benzyl) the chloro-1-chromene of-4-methyl-6-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2,6-bis-fluoro-3-cyclopropylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (methylaminocarbonylmethyl) amino-sulfonyl of N, N-) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(dimethylaminocarbonylmethyl amino-sulfonyl) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (amino carbonyl methyl) amino-sulfonyl of N, N-) methylaminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2,6-bis-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(dimethylamino alkylidene amino alkylsulfonyl) benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(dimethylaminopropylamino alkylsulfonyl) benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(amino carbonyl methyl amino-sulfonyl) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(Dimethylaminoethylamino alkylsulfonyl) benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (amino carbonyl methyl) amino-sulfonyl of N, N-) benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-dimethylamino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-cyclopropylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (methylaminocarbonylmethyl) amino-sulfonyl of N, N-) benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (methylaminocarbonylmethyl) amino-sulfonyl of N, N-) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(amino carbonyl methyl amino-sulfonyl) benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(3-(two (amino carbonyl methyl) amino-sulfonyl of N, N-) benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2,6-bis-fluoro-3-dimethylamino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-methyl piperidine base Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-phenylsulfamoyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-morpholinyl Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-methylaminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-methylaminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-methyl piperidine base Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-cyclopropylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-tert-butyl carbonyl diazanyl Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-propionyl diazanyl Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-chloro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
N-methyl-N ethyl-carboxylamine 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Morpholine formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Piperidine carboxylic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
N-Methyl-N-phenyl-carboxylamine 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Diisopropylaminoethyl formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the chloro-6-of 4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-7-of-4-methyl-6-(to methylpyrimidine-2-base oxygen base)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-7-of-4-methyl-6-(to ethyl-pyrimidine-2-base oxygen base)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-7-(to methylpyrimidine-2-base oxygen base)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-7-(to ethyl-pyrimidine-2-base oxygen base)-2-oxo-2H-1-chromene,
Dimethyl carbamic acid 2-oxo-2H-3-(2,4-bis-fluoro-3-aminosulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-diazanyl Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the fluoro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-hydroxyl-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-hydroxyethylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-Dimethylaminoethylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-tert-butylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-hydroxyl amino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-Dimethylaminocarbonyl amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-morpholinyl carbonylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-7-of-4-methyl-6-(to chloropyrimide-2-base oxygen base)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-7-of-4-methyl-6-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-kharophen Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-kharophen Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
3-(4-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl) the chloro-7-of-4-methyl-6-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-morpholinyl carbonylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
3-(4-fluoro-morpholinyl carbonylamino Sulphonylbenzyl) the chloro-7-of-4-methyl-6-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-methylpiperazine base carbonylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
3-(4-fluoro-morpholinyl carbonylamino Sulphonylbenzyl)-4-methyl-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl)-4-methyl-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-N-methylaminocarbonyl amino-sulfonyl benzyl) the chloro-7-of-4-methyl-6-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-N-methylaminocarbonyl amino-sulfonyl benzyl)-4-methyl-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethyl carbamic acid 2-oxo-2H-3-(2-fluoro-3-N-methylaminocarbonyl amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl) the chloro-1-chromene of-4-hydroxyethyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-hydroxypropyl Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methoxy ethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methoxy-propyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(morpholinyl ethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methylpiperazinylethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(piperidinoethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-carboxymethylamino Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(4-fluoro-3-carboxyethylamino group Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(amino carbonyl methyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methylaminocarbonylmethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(N, N-dimethylaminocarbonylmethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(N-methyl piperidine-4-base) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(pyridin-4-yl ethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(aminopropyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(amino-ethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(azetidine-3-base) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(pyrrolidin-3-yl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(piperidin-4-yl ethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 2-(hydroxyethylamino) Sulphonylbenzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methyl) (pyrrolidin-3-yl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(4-hydroxy cyclohexylphenyl alkyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methyl) (hydroxyethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(2,3-dihydroxypropyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(methylol) (hydroxyethyl) amino-sulfonyl benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester,
Dimethyl carbamic acid 2-oxo-2H-3-(the fluoro-3-of 4-(1-aminocarboxyl-2-hydroxyethylamino alkylsulfonyl) benzyl) the chloro-1-chromene of-4-methyl-6--7-base ester.
5. a pharmaceutical composition, is characterized in that: described pharmaceutical composition comprises compound according to any one of claims 1-4 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
6. the compound according to any one of claims 1-4 or the application of its pharmacy acceptable salt in the pharmaceutical composition preparing treatment cell proliferation disorders or inflammatory disease.
7. apply as claimed in claim 6, it is characterized in that: described cell proliferation disorders is selected from cancer.
8. apply as claimed in claim 7, it is characterized in that: described cancer is selected from melanoma, mammary cancer, colorectal carcinoma, carcinoma of the pancreas and lung cancer.
CN201210201758.2A 2011-06-17 2012-06-15 Coumarin derivatives and pharmaceutical composition thereof and purposes Active CN102827124B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201210201758.2A CN102827124B (en) 2011-06-17 2012-06-15 Coumarin derivatives and pharmaceutical composition thereof and purposes

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN2011101634674 2011-06-17
CN201110163467.4 2011-06-17
CN201110163467 2011-06-17
CN201210201758.2A CN102827124B (en) 2011-06-17 2012-06-15 Coumarin derivatives and pharmaceutical composition thereof and purposes

Publications (2)

Publication Number Publication Date
CN102827124A CN102827124A (en) 2012-12-19
CN102827124B true CN102827124B (en) 2015-10-21

Family

ID=47330462

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201210201758.2A Active CN102827124B (en) 2011-06-17 2012-06-15 Coumarin derivatives and pharmaceutical composition thereof and purposes

Country Status (2)

Country Link
CN (1) CN102827124B (en)
WO (1) WO2012171488A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107823200A (en) * 2017-11-14 2018-03-23 三峡大学 Inhibitor application on pharmacy of the coumarin derivative as KLK7
WO2020035058A1 (en) * 2018-08-17 2020-02-20 江苏新元素医药科技有限公司 Pharmaceutical compounds for treating liver diseases and application thereof
DE102019005196A1 (en) * 2019-07-25 2021-01-28 Forschungszentrum Jülich GmbH Process for the production of a coumarin-caged forskolin derivative, forskolin derivative and use of the forskolin derivative
CN118574826A (en) * 2022-01-26 2024-08-30 南京明德新药研发有限公司 Coumarin compound and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101384577A (en) * 2006-02-09 2009-03-11 中外制药株式会社 Novel coumarin derivative having antitumor activity

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002008217A2 (en) * 2000-07-21 2002-01-31 Chugai Seiyaku Kabushiki Kaisha COUMARIN DERIVATIVES USEFUL AS TNFα INHIBITORS
EP2172198B1 (en) * 2007-07-20 2014-04-16 Chugai Seiyaku Kabushiki Kaisha p27 PROTEIN INDUCER

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101384577A (en) * 2006-02-09 2009-03-11 中外制药株式会社 Novel coumarin derivative having antitumor activity

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Discovery and structure–activity relationship of coumarin derivatives as TNF-α inhibitors;Jie-Fei Cheng et al.;《Bioorg. Med. Chem. Lett.》;20041231;第14卷;2411–2415 *
Identification of coumarin derivatives as a novel class of allosteric MEK1 inhibitors;Shulin Han et al.;《Bioorg. Med. Chem. Lett.》;20050930;第15卷;5467–5473 *

Also Published As

Publication number Publication date
CN102827124A (en) 2012-12-19
WO2012171488A1 (en) 2012-12-20

Similar Documents

Publication Publication Date Title
CN102432663B (en) Celastrol derivative and preparation method thereof and application of celastrol derivative to preparation of antitumor medicine
JP5216083B2 (en) Azaindole-indole coupling derivatives and their preparation and use
CN102827124B (en) Coumarin derivatives and pharmaceutical composition thereof and purposes
CN107698657A (en) Bifunctional molecule and its preparation and application based on VHL parts and the induction BET degradeds of BET inhibitor
CN106831824A (en) Pyrrolopyridines and its application containing naphthyridones structure
CN105732615A (en) CDK kinase inhibitor
CN104230952B (en) Compound containing pyrimidine skeleton, and preparation method and use of compound
CN104829596A (en) Pyrrole-substituted indolinone derivative and preparation method thereof, composition including derivative, and application of derivative
CN106831812B (en) Simultaneously pyrimidine or pyrazine compounds and its application of the heterocycle of the amide structure containing biaryl
CN103420990A (en) 7-oxy, thio or imino substituted coumarin, and derivatives and applications thereof
CN105153190B (en) Heterocycle miazines compound of the amide structure containing biaryl and its preparation method and application
CN102746281A (en) 4-1,2,3-triazole-coumarin derivative and its preparation method and application
CN106083704A (en) 3,5 (E) two aryl methylene N cyclopropyl piperidine 4 ketone compounds is as the application of Hsp90 inhibitor
CN105175360A (en) Ether aryl piperazine derivatives, and salts, preparation methods and application thereof
CN105541859B (en) Dihydrofuran and chromanone derivatives and preparation method thereof and medical usage
CN101429183B (en) 2H-1-benzopyran-2-ketone compounds with alpha-glucosidase inhibit activity, its composition and preparation method thereof
CN111777577A (en) Taxol derivative and application thereof in preparation of medicine for preventing and treating human malignant tumor
CN113527391B (en) Catalpol derivative and preparation method and application thereof
CN100535000C (en) Method of preparing cyclopamine from jervine
CN113444074B (en) Compound with EGFR (epidermal growth factor receptor) and Wnt dual inhibition effects as well as preparation method and application thereof
CN108164476B (en) Isophthalonitrile compound, application thereof and medicine containing compound
CN104497008B (en) Substituted (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides compound and using method thereof and purposes
CN104402875A (en) Synthesis method and application N-(2-aminoethyl)-N&#39;-(6-substituted-2-benzothiazolyl)urea and salt compounds thereof
CN103172606A (en) Coumarin compound with anti-tumor activity
CN102268014A (en) Condensed heteroaryl derivative and its preparation method and use

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant