CN102827124A - Coumarins derivate and medicine composition thereof and application - Google Patents
Coumarins derivate and medicine composition thereof and application Download PDFInfo
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- CN102827124A CN102827124A CN2012102017582A CN201210201758A CN102827124A CN 102827124 A CN102827124 A CN 102827124A CN 2012102017582 A CN2012102017582 A CN 2012102017582A CN 201210201758 A CN201210201758 A CN 201210201758A CN 102827124 A CN102827124 A CN 102827124A
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—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
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
Abstract
The invention relates to a coumarins derivate with the following general formula (I), or pharmaceutically acceptable salt or solvate, wherein X, Y1, Y2, Y3, R1, R2, R3 and R4 are respectively defined as shown in an instruction book. The invention also relates to a medicine composition including compounds and an application of the compounds on treatment of tumor and/or inflammation.
Description
Technical field
The pharmaceutical composition and the purposes that the present invention relates to a kind of coumarins verivate, its pharmacy acceptable salt or solvolyte and contain them; More particularly, the present invention relates to a kind of have coumarins verivate, its pharmacy acceptable salt or the solvolyte of anti-tumor activity and anti-inflammatory activity and pharmaceutical composition and the purposes that contains them.
Background technology
Tonka bean camphor and verivate thereof are one type of lactone cpds that extensively is present in occurring in nature, and the difference according to its benzo α pyrone substitution in ring base is divided into simply usually, furans, pyrans and 4 kinds of other coumarin kind compounds.Coumarin kind compound has antitumor, and anti-HIV is anti-oxidant, antibiotic, arrhythmia, and osteoporosis, multiple biological activity such as anticoagulation (non-patent literature 1,2) is relievingd asthma in analgesia.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 progressively is deep on the molecular mechanism through the various kinds of cell model research; Mainly be through acting on the cell cycle, cell death inducing, the propagation (non-patent literature 2) of inhibition such as multiple signal pathway tumour cell.
Simple coumarins is only at tonka bean camphor phenyl ring one side C-6, C-7 or C-8 substd, and the C-7 position is total for containing the oxygen base.The osthole of having reported (non-patent literature 3,4) is to lung adenocarcinoma cell MK-1, A549, and heLa cell B16F10, liver cancer cell Bel-7402 all has obvious inhibiting activity.Aesculetin (non-patent literature 5,6) thus be in the news through inducing G1 phase cell-cycle arrest to suppress the propagation of leukemia cell HL-60.
The furocoumarin(e) class is 7 hydroxyls of coumarins composition and 6 or 8 bit substituents-isopentene group cyclization formation furan nucleus, and degraded has simultaneously lost 3 carbon atoms.The psoralene of having reported (non-patent literature 7) has good dose-dependent inhibition effect to breast cancer cell MCF-7; Decursin; Columbianadins etc. (non-patent literature 8-10) are to human stomach cancer cell line BGC cell; Human leukemia cell line HL-60 cell, people's epidermal carcinoma clone A-432 cell strain etc. has restraining effect in various degree.
Similar with furocoumarin(e), phenyl ring one is surveyed 7 hydroxyls and 6 or 8 bit substituents-isopentene group cyclization formation pyranoid ring, promptly belongs to the pyranocoumarin class.Praeruptorin C in this type of (Pra-C) is in the news and can impels white blood disease HL-60 apoptosis of tumor cells (non-patent literature 11,12).
On α pyrone ring, substituent coumarins is arranged; Coumarin dimer; The tripolymer class waits other coumarin kind compounds also to show good antitumor activity, thereby is in the news through suppressing the synthetic propagation (non-patent literature 13) that suppresses lung carcinoma cell of DNA like capillarin.
Remove the natural coumarin kind compound crowd of above introduction, the novel cpd crowd who is obtained by chemosynthesis also has report widely.For example, reported the compound (non-patent literature 14) that only on 7 of tonka bean camphor skeleton, has alkoxyl group; 7 and 8 at tonka bean camphor have substituting group and methyl substituted compound (non-patent literature 15) are arranged on 4; On 4 of tonka bean camphor skeleton, have arylalkyl, on 3 and 7, all have substituent compound (patent documentation 1); On 4 of tonka bean camphor skeleton, have phenyl, and on 3, have the compound (patent documentation 2) of phenoxy; The compound (non-patent literature 16) that on 5,6,7 of tonka bean camphor skeleton, has alkoxyl group; At 4,5,6,7 of tonka bean camphor skeleton, all has substituent compound (non-patent literature 17) on 8.
More than introduced the coumarin kind compound that much has 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 of Chinese 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 Xiaoxia, 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 tcm-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, white ice, 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 J Med 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 novel coumarin derivative or its pharmacologically acceptable salts or solvolyte with antitumor and anti-inflammatory activity, comprise the pharmaceutical composition of this verivate, and use.
According to an aspect of the present invention, the invention provides compound or its pharmacologically acceptable salts or solvolyte a kind of as following general formula (I) expression:
Wherein, X is selected from randomly by C
1-6Substituted heteroaryl of alkyl or halogen and R
5R
6NCO-,
Y
1, Y
2And Y
3Be independently selected from respectively-N=and-CR
7=;
R
1Be selected from H, halogen, C
1-6Alkyl;
R
2Be selected from randomly by the substituted C of hydroxyl
1-6Alkyl;
R
3And R
4, R
5, R
6Be independently selected from H, OH, NH respectively
2, C
1-6Alkyl, C
1-6Alkoxyl group, C
3-8Naphthenic base, C
6-10Aryl, heterocyclic radical ,-COR
8,-NHCOR
8,-CONR
9R
10, wherein said heterocyclic radical is randomly by OH or C
1-6Alkyl replaces, said C
1-6The substituting group that alkyl randomly is 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-; Perhaps
R
3And R
4Combination, R
5And R
6Combination, R
9And R
10Combination, R
11And R
12Combination can form randomly by C with the nitrogen-atoms that links to each other
1-6The substituted 4-6 unit heterocyclic radical that contains at least 1 nitrogen-atoms at least of alkyl; Perhaps
-NR
3R
4Form by two (C jointly
1-6Alkyl) amino substituted alkylidene amino;
R
5And R
6Be independently selected from H, C respectively
1-6Alkyl, C
3-8Naphthenic base, C
6-10Aryl; Perhaps R
5And R
6Combination form the 4-6 unit heterocyclic radical that contains 1 nitrogen-atoms at least with the nitrogen-atoms that links to each other;
R
7Be selected from H, OH, halogen, C
1-6Alkyl;
Each R
8Be independently selected from C
1-6Alkyl and heterocyclic radical;
Each R
9And R
10Be independently selected from H and C
1-6Alkyl, perhaps R
9And R
10Combination form randomly by C with the nitrogen-atoms that links to each other
1-6The substituted 4-6 unit heterocyclic radical that contains 1 nitrogen-atoms at least of alkyl.
According to an embodiment of the invention, the present invention relates to logical formula I compound or its pharmacy acceptable salt or solvolyte, it is characterized in that:
X is for randomly by C
1-6The substituted pyrimidine-2-base of alkyl or halogen;
Y
1, Y
2And Y
3Be independently-CR respectively
7=;
R
1Be selected from H, halogen, C
1-6Alkyl;
R
2Be selected from C
1-6Alkyl;
R
3And R
4Be independently selected from H, C respectively
1-6Alkyl ,-CONR
9R
10
R
7Be selected from H, halogen;
R
9And R
10Be independently selected from H and C
1-6Alkyl, perhaps R
9And R
10Combination form randomly by C with the nitrogen-atoms that links to each other
1-6The substituted 4-6 unit heterocyclic radical that contains 1 nitrogen-atoms at least of alkyl.
According to an embodiment of the invention, the present invention relates to logical formula I compound or its pharmacy acceptable salt or solvolyte, 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 independently-CR respectively
7=;
R
1Be selected from H, halogen, C
1-6Alkyl;
R
2Be selected from randomly by the substituted C of hydroxyl
1-6Alkyl;
R
3And R
4Be independently selected from H, OH, NH respectively
2, C
1-6Alkyl, C
3-8Naphthenic base, heterocyclic radical ,-COR
8,-NHCOR
8,-CONR
9R
10, wherein said heterocyclic radical is randomly by OH or C
1-6Alkyl replaces, said C
1-6The substituting group that alkyl randomly is selected from following group replaces: halogen, OH, COOH, NH
2, C
1-6Alkoxyl group, heterocyclic radical, heteroaryl ,-COOR
8,-NR
9R
10With-CONR
9R
10Perhaps
R
3And R
4Combination form randomly by C with the nitrogen-atoms that links to each other
1-6The substituted 4-6 unit heterocyclic radical that contains at least 1 nitrogen-atoms at least of alkyl;
R
7Be selected from H, OH, halogen;
Each R
8Be independently selected from C
1-6Alkyl and heterocyclic radical;
Each R
9And R
10Be independently selected from H and C
1-6Alkyl, perhaps R
9And R
10Combination form randomly by C with the nitrogen-atoms that links to each other
1-6The substituted 4-6 unit heterocyclic radical that contains 1 nitrogen-atoms at least of alkyl.
According to another embodiment of the present invention, logical formula I compound is selected from one of following compound:
Dimethylamino formic acid 2-oxo-2H-3-(3-methylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, N-dimethylamino carbonyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-sec.-propyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(sec.-propyl amino-sulfonyl) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-methylamino Sulphonylbenzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-methylamino Sulphonylbenzyl)-4-methyl-basic ester of 6-methyl isophthalic acid-chromene-7,
Pyrimidine-2-base 2-oxo-2H-3-(3-methylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ether,
Dimethylamino formic acid 2-oxo-2H-3-(3-methylamino Sulphonylbenzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(ethyloic) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(hydroxypropyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(methylamino carbonyl methyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(ethoxy carbonyl ethyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(hydroxyethyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethylamino carbonyl methyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(2,2, the 2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(amino carbonyl methyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(carboxy ethyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(2,2, the 2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(3,3, the 3-trifluoro propyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(2,2, the 2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(2,2, the 2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(6-fluoro-3-cyclopropyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(3,3, the 3-trifluoro propyl) amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(6-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-cyclopropyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-cyclopropyl amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(3,3, the 3-trifluoro propyl) amino-sulfonyl benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-cyclopropyl amino-sulfonyl benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(6-fluoro-3-(2,2, the 2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(6-fluoro-3-(dimethyl aminoethyl amino-sulfonyl) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethyl aminoethyl amino-sulfonyl) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (dimethyl aminoethyl) amino-sulfonyls of N-) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-cyclopropyl amino-sulfonyl benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(3,3,3-trifluoro propyl amino-sulfonyl) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethyl aminoethyl amino-sulfonyl) benzyl)-4-methyl-6 chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2,6-two fluoro-3-cyclopropyl amino-sulfonyl benzyls)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (the methylamino carbonyl methyl) amino-sulfonyls of N-) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethylamino carbonyl methylamino alkylsulfonyl) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (amino carbonyl methyl) amino-sulfonyls of N-) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2,6-two fluoro-3-amino-sulfonyl benzyls)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethylamino alkylidene amino alkylsulfonyl) benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethylaminopropyl amino-sulfonyl) benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(amino carbonyl methyl amino-sulfonyl) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethyl aminoethyl amino-sulfonyl) benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (amino carbonyl methyl) amino-sulfonyls of N-) benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-dimethylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-cyclopropyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (the methylamino carbonyl methyl) amino-sulfonyls of N-) benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (the methylamino carbonyl methyl) amino-sulfonyls of N-) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(amino carbonyl methyl amino-sulfonyl) benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (amino carbonyl methyl) amino-sulfonyls of N-) benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2,6-two fluoro-3-dimethylamino Sulphonylbenzyls)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-methyl piperidine base Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-phenylsulfamoyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-morpholinyl Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-methylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-methylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-methyl piperidine base Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-cyclopropyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-tertiary butyl carbonyl diazanyl Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-propionyl group diazanyl Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-chloro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
N-methyl-N-ethyl-carboxylamine 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Morpholine formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Piperidine carboxylic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
N-methyl-N-phenyl-carboxylamine 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Diisopropylaminoethyl formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-chloro-6-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-7-(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)-4-methyl-6-chloro-7-(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,
Dimethylamino formic acid 2-oxo-2H-3-(2,4-two fluoro-3-methylamino-Sulphonylbenzyls)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-diazanyl Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-hydroxyl-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-hydroxyethylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-dimethyl aminoethyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-tertiary butyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-hydroxyl amino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-dimethylamino carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-morpholinyl carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-7-(to chloropyrimide-2-base oxygen base)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-kharophen Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-kharophen Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
3-(4-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl)-4-methyl-6-chloro-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-morpholinyl carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
3-(4-fluoro-morpholinyl carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-N-METHYL PIPERAZINE base carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-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-methylamino carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-N-methylamino carbonylamino Sulphonylbenzyl)-4-methyl-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-N-methylamino carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-hydroxyethyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-hydroxypropyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(methoxy ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(methoxy-propyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(morpholinyl ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(N-METHYL PIPERAZINE base ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(piperidyl ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-carboxymethylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-propyloic amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(amino carbonyl methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(methylamino carbonyl methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(N, N-dimethylamino carbonyl methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(N-methyl piperidine-4-yl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(pyridin-4-yl ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(aminopropyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(amino-ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(azetidine-3-yl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(tetramethyleneimine-3-yl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(piperidin-4-yl ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-(hydroxyethylamino) Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(methyl) (tetramethyleneimine-3-yl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(4-hydroxyl cyclohexyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(methyl) (hydroxyethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(2, the 3-dihydroxypropyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(methylol) (hydroxyethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(1-aminocarboxyl-2-hydroxyethylamino alkylsulfonyl) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester.
According to a further aspect in the invention, pharmaceutical composition comprises logical formula I compound or its pharmacy acceptable salt or solvolyte 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 solvolyte, it is used to treat cell proliferation disorders or inflammation class disease.
According to a further aspect in the invention, the invention provides the application in the medicine of making treatment cell proliferation disorders and inflammation class disease of logical formula I compound or its pharmacy acceptable salt or solvolyte.
Cell proliferation disorders among the present invention is the disease of the common indication in this area, and it can be selected from tumour, especially is selected from cancer.Described cancer includes but not limited to liver cancer, cancer of the stomach, esophagus cancer, leukemia (white blood disease), 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 embodiments of the present invention, said cancer is melanoma, mammary cancer, colorectal carcinoma, carcinoma of the pancreas or lung cancer.
Term definition:
" alkyl " as the group or the part of other groups, the substituted alkyl of halogen for example, substituted alkyl of hydroxyl or alkoxyl group, can be straight chain or side chain.C
1-6Alkyl is represented 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 " is meant monocycle or the condensed aromatic ring that comprises six to ten carbon atoms.The instance of aryl comprises phenyl and naphthyl, wherein preferred phenyl.
" heteroaryl " is meant any condensing or the aromatic ring system of non-condensed, and wherein at least one ring is to contain 1-4 to be selected from nitrogen, and heteroatomic five of oxygen and sulphur arrives octatomic ring, and preferably at least one heteroatoms is selected from nitrogen.The instance of heteroaryl includes but not limited to thienyl, imidazolyl, pyrazolyl, thiazolyl ， oxazolyl ， isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, benzimidazolyl-, benzopyrazoles base, indyl etc.
" naphthenic base " is meant saturated or part undersaturated monocycle, condensed ring or the bridged ring that comprises the carbon atom that specifies number.C for example
3-8Naphthenic base is meant the naphthenic base of three to eight carbon, comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
" heterocyclic radical " is meant defined naphthenic base among the present invention, wherein one or more the ring on carbon atom by oxygen, nitrogen ,-NR-, sulphur, carbonyl ,-S (O)-Huo – S (O)
2Replace Deng group.For example, heterocyclic radical can be for comprising 1 to 33 to 8 yuan of member ring systems that are selected from nitrogen, oxygen, sulphur.The instance of Heterocyclylalkyl includes but not limited to morpholinyl, pyrrolidyl, piperazinyl, piperidyl, thio-morpholinyl etc.
" alkylidene amino " is meant to have-group of N=C-R structure, and wherein R is the defined alkyl of preceding text.
" pharmaceutically acceptable carrier " is the inert carrier, auxiliary material, vehicle or the thinner that are used for pharmacy field of the common indication in this area.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, Ucar 35, polyoxyethylene glycol, vegetables oil; BSA; Gelatin, washing agent (for example polysorbas20, tween 80 etc.), solubilizing agent (for example, glycerine; Polyoxyethylene glycol etc.), inhibitor, sanitas, lipid acid, wax, weighting agent or tension force modifier, be used for covalently bound or with polymkeric substance, POLYACTIC ACID, Sodium bromoacetate homopolymer, SRU, hydrogel adhesive, liposome, microemulsion, multilamellar vesicle or the spheroplast agent of complexing of metal ion.
" solvolyte " be medicine in crystallisation process, because of solvent molecule adds the crystalline lattice is changed, the crystallization that obtains is called solvolyte, it includes but not limited to: hydrate, alcoholate and etherate.The solvolyte of above-mentioned logical formula I compound of the present invention is preferably pharmaceutically acceptable solvolyte, and it includes but not limited to the solvolyte that the second alcohol and water is become.
" pharmacy acceptable salt " is meant the pharmacologically acceptable salt of general formula of the present invention (I) compound.The example of these salt comprises and the mineral acid acid salt of hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid etc. for example; With the organic acid acid salt of formic acid, acetate, methylsulfonic acid, Phenylsulfonic acid, tosic acid, propionic acid, Hydrocerol A, succsinic acid, tartrate, fumaric acid, butyric acid, oxalic acid, propanedioic acid, toxilic acid, lactic acid, oxysuccinic acid, carbonic acid, L-glutamic acid, aspartic acid etc. for example; The salt that becomes with mineral alkali is as receiving salt, sylvite etc.; And with organic bases 2-monoethanolamine for example; L-arginine, Methionin, the salt that Tutofusin tris etc. form.
Use and pharmaceutical composition
Usually, The compounds of this invention can form suitable formulation with one or more pharmaceutically acceptable carriers and uses.These formulations are applicable to oral administration, rectal administration, and topical, and other parenteral routes are used (for example, subcutaneous, muscle, vein etc.).For example, the formulation of suitable oral administration comprises capsule, tablet, granule and syrup etc.The compound of the present invention that comprises in these preparations can be pressed powder or particle; Solution in water-based or the non-aqueous liquid or suspension; Water-in-oil or oil-in-water emulsion etc.Above-mentioned formulation can be processed via general practice of pharmacy by active compound and one or more carriers or auxiliary material.Above-mentioned carrier need be compatible with active compound or other auxiliary materials.For solid preparation, non-toxic carrier commonly used includes but not limited to N.F,USP MANNITOL, lactose, starch, Magnesium Stearate, Mierocrystalline cellulose, glucose, sucrose etc.The carrier that is used for liquid preparation comprises water, saline water, D/W, terepthaloyl moietie and polyoxyethylene glycol etc.Active compound can form solution or suspension with above-mentioned carrier.
Concrete administering mode and formulation depend on the physico-chemical property of compound itself and the severity of the disease of using etc.
Compsn of the present invention is prepared with the mode that meets the medical practice standard, quantitative and administration." significant quantity " that give compound by the concrete illness that will treat, the individuality of treatment, the cause of illness, the decision of factors such as the target spot of medicine and administering mode.Usually, general dosage through the gi tract external administration is 1-200mg/kg.The formulation of oral administration can contain 1-1000mg/kg compound of the present invention.
The compounds of this invention by above-mentioned logical formula I representative can be according to following operation, its similar operations, or other operations of describing in the document or its similar operations prepare.
The preparation of The compounds of this invention
Synthesis program
The synthetic method of logical formula I compound prepares shown in following scheme and embodiment:
Scheme one
Compound 2h in the scheme one and synthetic logical method describe in detail in the route map in scheme one,
1. wherein single two fluorine replace or do not have substituted 3-(chlorosulfonyl) phenylformic acid starting raw material 2a and cyclopropylamine reaction generation sulphonamide midbody 2b, and the alkali of use can be selected triethylamine for use, diisopropyl ethyl amine (DIPEA) etc.; Temperature of reaction is 0 to 70 degree centigrade, and reaction solvent can be selected THF (THF) for use, methylene dichloride (DCM) etc.; For example, phenylformic acid SULPHURYL CHLORIDE and methylamine are alkali with the triethylamine; THF is a solvent, and stirring at room obtained corresponding product in 3 hours.
2. sulfonamide benzoic acid midbody 2b is reduced into corresponding pure 2c under the effect of reductive agent, and reductive agent can be selected Peng Qinghuana (NaBH for use
4)/boron trifluoride, Peng Qinghuana (NaBH
4)/iodine (I
2), diborane (B
2H
6) etc., reaction solvent can be selected THF for use, temperature of reaction be 0 degree centigrade to room temperature.
3. the reaction of alcohol intermediate 2c and bromide reagent generates corresponding bromo cpd midbody 2d, and solvent is selected THF for use, and brominated reagent can be selected phosphorus tribromide (PCl for use
3), sulfuric acid/hydrogen bromide (H
2SO
4/ HBr), 0 degree centigrade of temperature of reaction is to room temperature, and the reaction times is 2-5 hour.
4. methyl aceto acetate is hydrogenated the sodium deprotonation earlier under subzero 10 to 0 degrees centigrade, obtains midbody 2e with bromide midbody 2d reaction at low temperatures subsequently, and solvent is selected THF for use.
5. midbody 2e and replacement or unsubstituted Resorcinol react under the strong acid dehydration conditions and generate coumarin kind compound midbody 2f, temperature of reaction be subzero 10 degrees centigrade to room temperature, reaction should be used the vitriol oil, the reaction times is 4 to 15 hours.
6. midbody 2f and N, N-dimethyl methyl acyl chlorides or other acyl chlorides be reacting generating compound midbody 2g under alkaline condition, and alkali can be selected salt of wormwood, yellow soda ash for use; Pottasium Hydroxide, sodium hydroxide, sodium hydride etc., solvent can be selected N for use; Dinethylformamide (DMF), THF, methylene dichloride; Tetracol phenixin etc., temperature of reaction be subzero 10 degrees centigrade to room temperature, the reaction times is 1 to 5 hour.
7. midbody 2g and halohydrocarbon react under alkaline condition and generate final product 2h, and alkali can be selected salt of wormwood, yellow soda ash, Pottasium Hydroxide for use; Sodium hydroxide, sodium hydride etc., solvent can be selected N for use; Dinethylformamide (DMF), THF (THF), methylene dichloride (DCM); Acetonitriles etc., temperature of reaction are-10 to 100 degrees centigrade, and the reaction times is 1 to 5 hour.
Scheme two
Compound 1i in the scheme two and synthetic logical method describe in detail in the route map in scheme two,
1. wherein starting raw material 1a generates midbody 1b through reduction reaction; Use the tetrahydrofuran solution of Peng Qinghuana and boron trifluoride dme etc.; Temperature of reaction be 0 degree centigrade to room temperature, reaction solvent can be selected THF (THF) for use, stirring at room obtained corresponding product in 3 hours.
2. midbody 1b and bromizating agent phosphorus tribromide prepare corresponding bromide 1c, and reaction solvent can be selected methylene dichloride for use, temperature of reaction be 0 degree centigrade to room temperature.
3. methyl aceto acetate is hydrogenated the sodium deprotonation earlier under subzero 10 to 0 degrees centigrade, obtains midbody 1d with bromide midbody 1c reaction at low temperatures subsequently, and solvent is selected THF for use.
4. midbody 1d and replacement or unsubstituted Resorcinol react under the strong acid dehydration conditions and generate coumarin kind compound midbody 1e, temperature of reaction be subzero 10 degrees centigrade to room temperature, reaction should be used the vitriol oil, the reaction times is 4 to 15 hours.
5. midbody 1e and acyl chlorides or halides are reacted under alkaline condition and are generated midbody 1f, and alkali can be selected salt of wormwood, yellow soda ash, Pottasium Hydroxide for use; Sodium hydroxide, sodium hydride etc., solvent can be selected N for use; Dinethylformamide (DMF), THF, methylene dichloride; Tetracol phenixin etc., temperature of reaction be subzero 10 degrees centigrade to room temperature, the reaction times is 1 to 15 hour.
6. midbody 1f reacts under ammonium chloride and zinc powder condition and generates midbody 1g, and solvent can be selected N for use, dinethylformamide (DMF), and THF, methyl alcohol, second alcohol and water etc., temperature of reaction is 70 degrees centigrade to 80 degrees centigrade, the reaction times is 2 to 15 hours.
7. diazotization reaction takes place in midbody 1g under Sodium Nitrite and sour condition; Cuprous chloride acetum reaction with saturated sulfurous gas generates midbody 1h again; Solvent can be selected hydrochloric acid (HCl) for use; Acetic acid (HAc) and water etc., temperature of reaction be subzero 10 degrees centigrade to room temperature, the reaction times is 2 to 5 hours.
8. midbody 1h generates final compound 1i with the reaction of amine substituent under alkaline condition, and alkali can be selected salt of wormwood, yellow soda ash for use; Pottasium Hydroxide, sodium hydroxide, sodium hydride etc.; Solvent can be selected N for use, dinethylformamide (DMF), THF; Methylene dichloride etc., temperature of reaction be 0 degree centigrade to room temperature, the reaction times is 1 to 15 hour.
Embodiment
Preparation embodiment
The described experiment of hereinafter, compound method and related midbody are to illustrate of the present invention, do not limit the scope of the invention.
Among the present invention the employed starting raw material of experiment or buy from reagent suppliers or via standard method by known feedstock production.Except as otherwise noted, the embodiment of this paper uses following condition:
1) unit of temperature be degree centigrade (℃); The definition of room temperature is 18-25 ℃;
2) organic solvent uses anhydrous magnesium sulfate or anhydrous sodium sulfate drying; Use Rotary Evaporators to do (for example: 15mmHg, 30 ℃) at decompression intensification condition underspin;
3) use during column chromatography for separation silica gel as carrier, TLC representes silica gel thin-layer plate;
4) generally, the progress of reaction is through TLC or LC-MS monitoring;
5) evaluation of the finished product by nucleus magnetic resonance (Bruker AVANCE 300,300MHz) and LC-MS (Bruker esquine 6000, Agilent 1200series);
Embodiment 1: dimethylamino formic acid 2-oxo-2H-3-(3-N, N-dimethyl aminoethyl amino-sulfonyl benzyl)-4- Methyl-6-chloro-1-chromene-7-base ester (title compound 2.8)Synthetic
The synthetic of title compound 2.8 prepares according to the program of describing in the scheme one.
3-(N-cyclopropyl amino-sulfonyl) phenylformic acid (2.2):
With cyclopropylamine (0.26g; 4.53mmol) and triethylamine (1.38g 13.6mmol) is dissolved in THF (15ml), under 0 ° of C condition, drips 3-(chlorosulfonyl) phenylformic acid (1g to this solution; 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 the TLC detection reaction finishes; Reaction solution is poured in the saturated aqueous common salt of 30mL, then with the hydrochloric acid soln of 1N handle to PH=3. with ETHYLE ACETATE (20mL * 2) extraction, organic layer is used the saturated common salt water washing; Anhydrous sodium sulfate drying; The decompression desolvate shallow white solid (title compound 2.2,0.6g, 55%).
3-(methylol)-N-cyclopropyl-phenyl sulphonamide (2.3):
With Peng Qinghuana (0.19g; 4.97mmol) be dissolved in THF (5ml); Under 0 ° of C condition, drip the tetrahydrofuran solution (5mL) of 3-(N-cyclopropyl amino-sulfonyl) phenylformic acid (0.6g, 2.49mmol, title compound 2.2) and under 0 ° of C condition, stir 0.5h to this solution; Then under 0 ° of C condition to this solution drip boron trifluoride dme solution (0.57g, 4.97mmol).After being added dropwise to complete, be warmed up to room temperature and stirred overnight at ambient temperature.After TLC and MS detection reaction finish,, extract with ETHYLE ACETATE (10mL * 2) with hydrochloric acid soln (3ml) cancellation of reaction solution with 1N.Organic layer is used the saturated common salt water washing successively, and anhydrous sodium sulfate drying removes solvent under reduced pressure and gets 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 THF (20ml), under 0 ° of C condition to this solution drip phosphorus tribromide (0.89g, 3.3mmol).After being added dropwise to complete, be warmed up to room temperature, and stir 3h at ambient temperature.After TLC and MS detection reaction finished, reaction solution extracted with ETHYLE ACETATE (20mL * 2).Organic layer is successively with saturated sodium bicarbonate solution washing, the saturated common salt water washing, anhydrous sodium sulfate drying, decompression desolvate yellow oil (title compound 2.4,0.87g, 91%).
2-(3-cyclopropyl amino-sulfonyl benzyl)-3-ethyl ketone (2.5):
(60%wt 11.4mmol) is dissolved in the 30ml THF for NaH, 0.45g, and cryosel is bathed and is cooled to 0 ° of C to take by weighing sodium hydride.(1.18g 9.10mmol), keeps 0 ° of C to stir 1h under 0 ° of C, in this solution, to splash into methyl aceto acetate.Under 0 ° of C condition, in this solution, drip the tetrahydrofuran solution (20ml) of 3-(brooethyl)-N-cyclopropyl-phenyl sulphonamide (2.2g, 7.58mmol, title compound 2.4) then, after dropwising, be warmed up to room temperature and stirred overnight.After TLC and MS detection reaction finish, reaction solution with saturated ammonium chloride solution (10ml) cancellation, is extracted with ETHYLE ACETATE (30mL * 2).Organic layer is used the saturated common salt water washing successively, anhydrous sodium sulfate drying, and decompression is desolvated, purified (normal hexane: ETHYLE ACETATE=10:1 ~ 3:1) must 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 by weighing 2-(3-cyclopropyl amino-sulfonyl benzyl)-3-ethyl ketone (0.5g; 1.47mmol, title compound 2.5) and 4-chlorine Resorcino (0.21g 1.47mmol) places tetracol phenixin (1ml); The vitriol oil of dropping below 0 ° of C (0.43g, 4.4mmol).After dropwising, the stirring at room reaction is spent the night.After the TLC detection reaction finishes, pour into and separate out white solid, suction filtration, ETHYLE ACETATE washing, the dry white solid (title compound 2.6,0.5623g, 41%) that gets in the frozen water.
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.
Dimethylamino formic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester
(2.7):
Take by weighing 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) places THF (10ml), in this solution, drips N under the ice bath; N-dimethyl methyl acyl chlorides (57mg, 0.583mmol).After dropwising, refluxing and stirring is spent the night.After the TLC detection reaction finishes, with reaction solution pour in the water (20ml), with ethyl acetate extraction, anhydrous sodium sulfate drying, remove that solvent gets bullion, recrystallization gets white solid (title compound 2.7,0.14g, 58%) under reduced pressure.
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
Dimethylamino formic acid 2-oxo-2H-3-(3-N, N-dimethyl aminoethyl amino-sulfonyl benzyl)-4-methyl-6-chlorine
-1-chromene-7-base ester (2.8):
Take by weighing dimethylamino formic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester (50mg; 0.12mmol; Title compound 2.7), N, N-dimethyl--2-chloroethyl amine (17.3mg, 0.12mmol) and salt of wormwood (50mg; 0.36mmol) place acetonitrile (3ml), with stirred overnight under the mixture room temperature of gained.After the TLC detection reaction finishes, reaction solution is leached, gets white solid (title compound 2.8,15mg, 23%) through the 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: dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(piperidyl ethyl) amino-sulfonyl benzyl)-4- Methyl-6-chloro-1-chromene-7-base ester (title compound 13)Synthetic
The synthetic of title compound 13 prepares according to the program of describing in the scheme two.
4-fluoro-3-oil of mirbane methyl alcohol (2):
(22.6g 590mmol) is dissolved in the 700ml THF, and cryosel is bathed and is cooled to 0 ° of C with Peng Qinghuana.Under 0 ° of C, in this solution, add 4-fluoro-3-nitrobenzoic acid (100g, 540mmol, title compound 1) in batches, keep 0 ° of C to stir 1h.Again 0 ° of C in above solution, splash into the boron trifluoride dme tetrahydrofuran solution (54.2mL, 590mmol), after dropwising, in room temperature reaction 3h.The TLC detection reaction, after reaction finished, frozen water cancellation reaction was used ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying.Remove desolvate white solid (title compound 2,90g, 97.4%).
4-(brooethyl)-1-fluoro-2-oil of mirbane (3):
4-fluoro-3-oil of mirbane methyl alcohol (50g, 290mmol, title compound 2) is dissolved in the 500ml methylene dichloride, and cryosel is bathed and is cooled to 0 ° of C.Under 0 ° of C, in this solution, dropwise splash into phosphorus tribromide (27.5mL, 290mmol), in room temperature reaction 2h.The TLC detection reaction, after reaction finished, frozen water cancellation reaction was used dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying.Remove desolvate yellow solid, through recrystallization purifying (normal hexane: ETHYLE ACETATE=1:1), white solid (title compound 3,54g, 79.9%).
2-(3-nitro-4-luorobenzyl)-3-ethyl ketone-(5):
(NaH, 13.8g 345mmol) are dissolved in the 400ml THF, and cryosel is bathed and is cooled to 0 ° of C to take by weighing sodium hydride.Under 0 ° of C, in this solution, splash into methyl aceto acetate (32.0mL, 250mmol, title compound 4), keep 0 ° of C to stir 1h.In above solution, splash into the 100ml tetrahydrofuran solution of 4-(brooethyl)-1-fluoro-2-oil of mirbane (54g, 230mmol, title compound 3) again at 0 ° of C, after dropwising, in stirred overnight at room temperature.The TLC detection reaction, after reaction finished, frozen water cancellation reaction was used ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying.Remove the bullion that desolvates, through purification by silica gel column chromatography (normal hexane: ETHYLE ACETATE=10:1 ~ 5:1), get yellow oil (title compound 5,36g, 55.4%).
3-(4-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-6-chloro-2-oxo-2H-2-chromene (7):
Take by weighing 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 the cryosel bath, drip the vitriol oil (20.3ml) below 0 ° of C; After dropwising, the stirring at room reaction is spent the night.The TLC detection reaction after reaction finishes, is poured in the frozen water, separates out white solid, suction filtration, and drying gets white solid (title compound 7,29g, 65.9%).
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-nitrobenzyl)-4-methyl-6-chloro-1-chromene-7-base ester (9):
Take by weighing 3-(4-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-6-chloro-2-oxo-2H-2-chromene (29g, 83.7mmol, title compound 7) and be dissolved in 200ml THF and the 50ml water, cryosel is cooled to-10 ° of C under bathing.In this solution, add salt of wormwood (57.8g, 418.5mmol), after adding finished, the stirring at room reaction was spent the night in batches.The TLC detection reaction after reaction finishes, is poured in the frozen water, separates out white solid, suction filtration, and drying gets bullion, through recrystallization purifying (ethanol), gets white solid (title compound 9,30g, 82.6%).
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-aminobenzyl)-4-methyl-6-chloro-1-chromene-7-base ester (10):
Take by weighing dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-nitrobenzyl)-4-methyl-6-chloro-1-chromene-7-base ester (30g; 78.3mmol, title compound 9) and be dissolved in N, dinethylformamide (DMF; 200ml), cryosel is cooled to-10 ° of C under bathing.In this solution, add respectively ammonium chloride (21.7g, 391.5mmol) and zinc powder (10.2g, 156.6mmol), add finish after, heating reflux reaction spends the night.The TLC detection reaction after reaction finishes, removes by filter white solid.Filtrating is poured in the frozen water, separates out white solid, suction filtration, drying, white solid (title compound 10,40g, 100%).
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-chlorosulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester
(11):
At reaction flask 1; Take by weighing dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-aminobenzyl)-4-methyl-6-chloro-1-chromene-7-base ester (20g; 54.0mmol, title compound 10) be dissolved in 100mL hydrochloric acid and the 50mL acetic acid, cryosel is cooled to-10 ° of C under bathing.(3.72g, aqueous solution 54.0mmol) after adding finishes, keep-10 ° of C to stir 1h in this solution, dropwise to add Sodium Nitrite.In another three-necked bottle 2, (1.34g 13.5mmol) is dissolved in the 100mL acetic acid to take by weighing cuprous chloride; Room temperature feeding sulfur dioxide gas to solution is saturated; With reaction cooled to 0 ° C, the solution of refrigerative reaction flask 1 is dropwise joined in the reaction flask 2, dropwise and continue room temperature reaction 2h.The TLC detection reaction after reaction finishes, is poured filtrating in the frozen water into, separates out yellow solid, and suction filtration gets bullion, through purification by silica gel column chromatography (methylene dichloride), gets white solid (title compound 11,5g, 20.7%).
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(piperidyl ethyl) amino-sulfonyl benzyl)-4-methyl-6-chlorine
-1-chromene-7-base ester (13):
Taking by weighing dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-chlorosulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester (400mg, 0.84mmol, title compound 11) is dissolved in the 10ml THF; In this solution, add salt of wormwood (347.8g, 2.52mmol), cryosel is bathed 0 ° of C of cooling down; Dropwise add 1-piperidine-1-ethanamine (126mg, 1.68mmol, title compound 12); After adding finished, the stirring at room reaction was spent the night.The TLC detection reaction after reaction finishes, is poured in the frozen water, uses ethyl acetate extraction; The saturated common salt water washing, anhydrous sodium sulfate drying, remove desolvate bullion; Through purification by silica gel column chromatography (methylene dichloride: methyl alcohol=1:0 ~ 10:1) white solid (title compound 13,100mg, 20.6%).
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: dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-(2-hydroxyethyl)-6-chloro-1- Chromene-7-base esterSynthetic
Take by weighing dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester (468mg, 1mmol), be dissolved in THF (THF, 120ml) in, be cooled to-78 ° of C under the nitrogen protection.(1mol/L, 3.2ml 3.2mmol), after adding finishes, keep stirring one hour below-78 ° of C in this solution, to be added dropwise to hexamethyl two silica-based Lithamides.(30mg, (THF 3ml), is added drop-wise in the low-temp reaction liquid, after dropwising, rises to room temperature gradually, stirred overnight 1mmol) to dissolve in THF with Paraformaldehyde 96.The TLC detection reaction after reaction finishes, adds 20mLH in reaction solution
20, use ethyl acetate extraction, anhydrous sodium sulfate drying.Remove the bullion that desolvates,, get white solid (56mg, 11.2%) through silica gel column chromatography.
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 for preparing:
Under the listed compound of tabulating utilize similar starting raw material to prepare through being similar to method mentioned above:
Table one
Number 018,025,027,036,037,039,044,045 in the above-mentioned table one, 053 compound is prepared from through scheme one, numbers 112 compounds and is prepared from through scheme two and embodiment 3 methods, and all the other compounds are prepared from through scheme two.
Effect embodiment
To the test experience that the present invention relates to compound
1. growth of tumour cell suppresses experiment
Materials and methods
It is following that growth of tumour cell of the present invention suppresses the experiment material requested
Table twoShown in, cell source wherein is CAS (Chinese Academy of Sciences's Shanghai cell bank), and (DojinDo CK04-20) detects the cell growth through the CCK-8 detection reagent.
Table two
Cell inoculation: with the cell of 0.25% trysinization logarithmic phase.RPMI1640 substratum with containing 10%FBS is made into single cell suspension.Invitrogen Countess carries out cell counting.Be inoculated in 96 orifice plates by last table cell title and inoculation number/hole/100uL.The blank group adds the 100uL substratum.Culture plate is put in the incubator, 37 ℃, 5%CO
2Overnight cultures.
Drug-treated: each testing sample begins from 10uM, and 5 times of dilutions are provided with 6 drug levels, and each concentration is done 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 that contains 2 times of medicine final concentrations to be measured, the 100uL/ hole.96 orifice plates are put back to incubator, 37 ℃, 5%CO
2Act on 72 hours.Control group adds the not substratum of drug.
Colour developing and IC
50Calculating: after effect in 72 hours finishes, in incubator, take out 96 orifice plates, discard the substratum hole in, adding contains the fresh culture of 10%CCK-8,100uL/ hole.After adding, 96 orifice plates are put back in the incubator, continued to cultivate 1-4h, significantly orange red until appearing.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 the logistic match with origin8, calculate the IC of counter sample
50Value, IC
50The growth-inhibiting of low more explanation medicine pair cell is obvious more.
Part of compounds in the table one is for the inhibition ability reference of MC 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 | ** |
* represent IC
50>1 μ M
* representes IC
50=0.1 μ M～1 μ M
* * representes IC
50=0.01 μ M～0.1 μ M
* * * representes IC
50<0.01 μ M
Above-mentioned vitro detection experimental data shows that formula of the present invention (I) above-claimed cpd has the activity that suppresses the A375 growth of tumour cell, the very strong activity of some compound exhibits wherein.
Part of compounds in the table one is for the inhibition 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 | ** |
* represent IC
50>1 μ M
* representes IC
50=0.1 μ M～1 μ M
Above-mentioned vitro detection experimental data shows that formula of the present invention (I) above-claimed cpd has the activity that suppresses the Colo-205 growth of tumour cell.
With the part of compounds in the table one is that example detects the inhibition ability (reference of compound of the present invention to kinds of tumor cells
Table four):
Table four: active IC
50
* represent IC
50>1 μ M
* representes IC
50=0.1 μ M～1 μ M
* * representes IC
50=0.01 μ M～0.1 μ M
Above-mentioned vitro detection experimental data shows that the kinds of tumor cells growth in formula of the present invention (I) the representation compound his-and-hers watches four all has restraining effect.
With the part of compounds in the table one is that example is tested compound of the present invention for the (reference of Normocellular inhibition ability
Table five):
Table five
Above-mentioned vitro detection experimental data shows that formula of the present invention (I) representation compound does not have obvious restraining effect to normal cell Hs27, has good security.
2. stability study method (the mensuration side of compound external metabolic stability of compound of the present invention in hepatomicrosome
Method)
Compound dissolution of the present invention to be measured acetonitrile or acetonitrile-water (1/1, V/V) in, process the storing solution that concentration is 1mM.2 μ l storing solutions add in the centrifuge tube; Add 148 μ l phosphoric acid buffer (50mM then; PH 7.4) and 10 μ l hepatomicrosomes (protein concentration is 20mg/ml) suspension, in 37 ℃ of water-baths, incubated in advance 3 minutes behind the mixing, add 40 μ l NADPH generation system then and (contain 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, the concussion 3 minutes of mediating after in 37 ℃ of water-baths, hatching 0.5 hour; Centrifugal (13000rpm) 5 minutes gets supernatant and detects the residual drug concentration C with HPLC
r
0 minute response sample of parallel preparation: mixed system in 37 ℃ incubate in advance took out in 3 minutes after, add 400 μ l acetonitriles, add 40 μ l NADPH then system take place.Mediate concussion after 3 minutes, centrifugal 5 minutes, get supernatant with HPLC detection of drugs concentration C
0
The residue per-cent of medicine in incubation system is according to computes:
Medicine residue (%)=C
r÷ C
0* 100%
With the part of compounds in the table one is the hepatomicrosome stability (with reference to table six) of example test The compounds of this invention:
Table six
Table six test experience data show that formula of the present invention (I) representation compound is more stable under the hepatomicrosome environment.
3. compound is in the intravital pharmacokinetics research of rat
After male SD rat is bought in, raised 7 days in this laboratory flexibility.8 SD rats are divided into 2 groups at random, and 4 every group, one group is used for gastric infusion, and another group is used for the tail vein injection administration.Need overnight fast before the rat of gastric infusion group, administration.After the rat administration, the method that adopts the blood sampling of eye socket venous plexus is at following time point blood sample collection: 0min (before the 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 of gathering with the centrifugal 5min of the rotating speed of 12000rpm, is gathered the upper plasma sample at 4 ° of C then, and in-20 ° of C refrigerators, preserves to be measured.Experimental implementation is summed up and is seen the following form seven:
Table seven
Use this breadboard LC-MS/MS to detect the compound concentration in the blood plasma.Use this breadboard pharmacokinetics professional software WinNonlin to calculate pharmacokinetic parameter.
With compound in the table one 053 is that example has been carried out bioavailability study, and the bioavailability of measuring this compound as stated above is 98%, shows that this compound has good oral administration biaavailability.
4. animal tumor growth-inhibiting experiment
Dilution was certain density cell suspension after the digestion of the cell (table two is seen in the source) of monolayer culture taken off wall, and it is subcutaneous to transplant in the nude mice right side trunk with the 1ml syringe.Treat that gross tumor volume grows to 500-600mm
3After, after knurl taken out, cut, select well-grown and do not have degeneration necrosis, be and talk tumor tissue red, flesh of fish shape, be cut into small pieces (about 5 * 5 * 5mm); Cut off-individual osculum in the nude mice back part of animal outside, send in the otch knurl piece subcutaneous with the 12G inoculating needle.The knurl piece passes 2-3 after generation, can be used for the pharmacodynamics evaluation of antitumor drug.Treat that the tumor-bearing mice gross tumor volume grows to 100-150mm
3, with tumor growth preferably animal carry out random packet, and the beginning administration, dosage regimen sees the following form eight.The measurement number of times of diameter of tumor is decided according to the growing state of transplanted tumor after dividing into groups, and is generally 2-3 time weekly, and each the measurement need claim also that simultaneously mouse is heavy.The gross tumor volume calculation formula is: TV (mm
3)=major diameter (a) * minor axis (b)
2/ 2.Generally finish experiment after 24 to 48 hours in the last administration, and calculate and respectively organize inhibition rate of tumor growth, calculation formula is TGI=(TV
Ctrl-TV
Tre)/TV
Ctrl* 100%.
Table eight
| Nude mice quantity | Measure medicine | Dosage | The administration volume | Route of administration | The administration cycle |
| 8 | 053 | 100mg/kg | 10ul/g | p.o. | Bidx14 |
With compound in the table one 053 is example, has carried out the research of animal tumor growth-inhibiting experiment, and the TGI that measures by the method for above-mentioned table eight is: A375,77%; MDA-MB-231,65.6%; Bx-PC-3,75%, do not see in the experiment that tangible the weight of animals reduces phenomenon, shows that this compound has good anti-tumor in vivo drug effect, possesses good security simultaneously.
5. extracorporeal anti-inflammatory activity experiment
1. experiment material
1.1. clone
RAW264.7 (mouse macrophage; ATCC No.TIB-71) purchases consonance medical university in Beijing
1.2. substratum
DMEM (Gibco#11995) interpolation 10% foetal calf serum (FBS, Gibco#)
1.3. reagent
LPS (Sigma, #L6529-1MG); Mouse TNF-α ELISA test kit (DKW12-2720-096)
1.4. equipment
Cell counter (invitrogen, C10227); ELIASA (Tecan IF200)
2. experimental technique
2.1. cell inoculation
With 3 * 10
5The density inoculation RAW264.7 cell in individual/100 μ l/ holes was cultivated about 6 hours for 37 ℃ in 96 orifice plates.
2.2. medicine pre-treatment: final concentration with 5 times of gradient dilutions of cell culture medium, is provided with 6 concentration point since 50 μ M, two multiple holes, pre-treatment 2 hours.
2.3.LPS stimulate: add the LPS that final concentration is 30ng/ml, about 16 hours of irritation cell.
2.4.TNF-α detects
LPS stimulated after 16 hours, and 3, the centrifugal 10min of 000rpm collects the nutrient solution supernatant and dilutes about 100 times, uses mouse; TNF-α ELISA test kit detects the TNF-alpha levels.
2.5. interpretation of result
Excel?2007，OriginPro?8.0.
3.ELISA use
3.1. before using,, avoid producing foam with the abundant mixing of all reagent.
3.2., confirm required lath number according to experimental port (blank and standard substance) quantity.Sample (containing standard substance) and blank all should be done multiple hole.
3.3. application of sample: the TNF-α standard substance after the adding dilution of 100ul/ hole are to the standard substance hole, and the 100ul/ hole adds sample to sample well, and blank well is set.
3.4. add detection antibody: the 50ul/ hole adds the biotinylated antibody after the dilution.Behind the mixing, cover the shrouding film, 37 ℃ of incubation 90min.
3.5. wash plate: button removes liquid in the hole, and the 300ul/ hole adds 1 * lavation buffer solution; Discard liquid in the hole after stopping 1min.Repeat 4 times, on filter paper, buckle and do.
3.6. enzyme-added: the 100ul/ hole adds the Streptavidin-HRP after the dilution.Cover the shrouding film, 37 ℃ of incubation 30min.
3.7. wash plate: button removes liquid in the hole, and the 300ul/ hole adds 1 * lavation buffer solution; Discard liquid in the hole after stopping 1min.Repeat 4 times, on filter paper, buckle and do.
3.8. colour developing: the 100ul/ hole adds TMB, and 37 ℃ of lucifuge incubation 20min add stop buffer, measures the 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,J?Crohns?Colitis,6,215-225.
Sae-Wong,C.,et?al.(2011)Suppressive?effects?of?methoxyflavonoids?isolated?from?Kaempferia?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-releasing?molecules?2?on?the?activation?of?Janus?kinase/signal?transducer?and?activator?of?transcription?pathway?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?inhibit?Src?and?spleen?tyrosine?kinase?activity?contributes?to?its?anti-inflammatory?action,J?Ethnopharmacol,139,566-573.
With compound in the table one 053 is example, has carried out the active research that suppresses experiment of above-mentioned extracorporeal anti-inflammatory, its EC
50For: 86nM shows that this compound has the good in vitro anti-inflammatory activity.
Those skilled in the art should recognize change and the retouching of under the situation that does not break away from appended scope of the present invention that claim disclosed of the present invention and spirit, being done, and all belong within the protection domain of claim of the present invention.
Claims (8)
1. compound and a pharmacologically acceptable salts or solvolyte of representing by following logical formula I:
Wherein, X is selected from randomly by C
1-6Substituted heteroaryl of alkyl or halogen and R
5R
6NCO-;
Y
1, Y
2And Y
3Be independently selected from respectively-N=and-CR
7=;
R
1Be selected from H, halogen, C
1-6Alkyl;
R
2Be selected from randomly by the substituted C of hydroxyl
1-6Alkyl;
R
3And R
4Be independently selected from H, OH, NH respectively
2, C
1-6Alkyl, C
3-8Naphthenic base, C
6-10Aryl, heterocyclic radical ,-COR
8,-NHCOR
8,-CONR
9R
10, wherein said heterocyclic radical is randomly by OH or C
1-6Alkyl replaces, said C
1-6The substituting group that alkyl randomly is selected from following group replaces: halogen, OH, COOH, NH
2, C
1-6Alkoxyl group, heterocyclic radical, heteroaryl ,-COOR
8,-NR
9R
10With-CONR
9R
10Perhaps
R
3And R
4Combination form randomly by C with the nitrogen-atoms that links to each other
1-6The substituted 4-6 unit heterocyclic radical that contains 1 nitrogen-atoms at least of alkyl; Perhaps
-NR
3R
4Form by two (C jointly
1-6Alkyl) amino substituted alkylidene amino;
R
5And R
6Be independently selected from H, C respectively
1-6Alkyl, C
3-8Naphthenic base, C
6-10Aryl; Perhaps R
5And R
6Combination form the 4-6 unit heterocyclic radical that contains 1 nitrogen-atoms at least with the nitrogen-atoms that links to each other;
R
7Be selected from H, OH, halogen, C
1-6Alkyl;
Each R
8Be independently selected from C
1-6Alkyl and heterocyclic radical;
Each R
9And R
10Be independently selected from H and C
1-6Alkyl, perhaps R
9And R
10Combination form randomly by C with the nitrogen-atoms that links to each other
1-6The substituted 4-6 unit heterocyclic radical that contains 1 nitrogen-atoms at least of alkyl.
2. compound as claimed in claim 1 or its pharmacy acceptable salt or solvolyte is characterized in that:
X is for randomly by C
1-6The substituted pyrimidine-2-base of alkyl or halogen;
Y
1, Y
2And Y
3Be independently-CR respectively
7=;
R
1Be selected from H, halogen, C
1-6Alkyl;
R
2Be selected from C
1-6Alkyl;
R
3And R
4Be independently selected from H, C respectively
1-6Alkyl ,-CONR
9R
10
R
7Be selected from H, halogen;
R
9And R
10Be independently selected from H and C
1-6Alkyl, perhaps R
9And R
10Combination form randomly by C with the nitrogen-atoms that links to each other
1-6The substituted 4-6 unit heterocyclic radical that contains 1 nitrogen-atoms at least of alkyl.
3. compound as claimed in claim 1 or its pharmacy acceptable salt or solvolyte 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 independently-CR respectively
7=;
R
1Be selected from H, halogen, C
1-6Alkyl;
R
2Be selected from randomly by the substituted C of hydroxyl
1-6Alkyl;
R
3And R
4Be independently selected from H, OH, NH respectively
2, C
1-6Alkyl, C
3-8Naphthenic base, heterocyclic radical ,-COR
8,-NHCOR
8,-CONR
9R
10, wherein said heterocyclic radical is randomly by OH or C
1-6Alkyl replaces, said C
1-6The substituting group that alkyl randomly is selected from following group replaces: halogen, OH, COOH, NH
2, C
1-6Alkoxyl group, heterocyclic radical, heteroaryl ,-COOR
8,-NR
9R
10With-CONR
9R
10Perhaps
R
3And R
4Combination form randomly by C with the nitrogen-atoms that links to each other
1-6The substituted 4-6 unit heterocyclic radical that contains at least 1 nitrogen-atoms at least of alkyl;
R
7Be selected from H, OH, halogen;
Each R
8Be independently selected from C
1-6Alkyl and heterocyclic radical;
Each R
9And R
10Be independently selected from H and C
1-6Alkyl, perhaps R
9And R
10Combination form randomly by C with the nitrogen-atoms that links to each other
1-6The substituted 4-6 unit heterocyclic radical that contains 1 nitrogen-atoms at least of alkyl.
4. compound as claimed in claim 1 or its pharmacy acceptable salt or solvolyte is characterized in that, it is one of following that said compound is selected from:
Dimethylamino formic acid 2-oxo-2H-3-(3-methylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, N-dimethylamino carbonyl) (methyl) amino-sulfonyl) benzyl-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-sec.-propyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(sec.-propyl amino-sulfonyl) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-methylamino Sulphonylbenzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-methylamino Sulphonylbenzyl)-4-methyl-basic ester of 6-methyl isophthalic acid-chromene-7,
Pyrimidine-2-base 2-oxo-2H-3-(3-methylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ether,
Dimethylamino formic acid 2-oxo-2H-3-(3-methylamino Sulphonylbenzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(ethyloic) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(hydroxypropyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(methylamino carbonyl methyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(ethoxy carbonyl ethyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(hydroxyethyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethylamino carbonyl methyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(2,2, the 2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(amino carbonyl methyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(carboxy ethyl) (methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(2,2, the 2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(3,3, the 3-trifluoro propyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(2,2, the 2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(2,2, the 2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(6-fluoro-3-cyclopropyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(3,3, the 3-trifluoro propyl) amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(6-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-cyclopropyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-cyclopropyl amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(3,3, the 3-trifluoro propyl) amino-sulfonyl benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-cyclopropyl amino-sulfonyl benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(6-fluoro-3-(2,2, the 2-trifluoroethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(6-fluoro-3-(dimethyl aminoethyl amino-sulfonyl) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N-dimethyl aminoethyl amino-sulfonyl) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (dimethyl aminoethyl) amino-sulfonyls of N-) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-cyclopropyl amino-sulfonyl benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(3,3,3-trifluoro propyl amino-sulfonyl) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethyl aminoethyl amino-sulfonyl) benzyl)-4-methyl-6 chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2,6-two fluoro-3-cyclopropyl amino-sulfonyl benzyls)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (the methylamino carbonyl methyl) amino-sulfonyls of N-) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethylamino carbonyl methylamino alkylsulfonyl) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (amino carbonyl methyl) amino-sulfonyls of N-) methylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2,6-two fluoro-3-amino-sulfonyl benzyls)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethylamino alkylidene amino alkylsulfonyl) benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethylaminopropyl amino-sulfonyl) benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(amino carbonyl methyl amino-sulfonyl) benzyl)-4-methyl-6-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(dimethyl aminoethyl amino-sulfonyl) benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (amino carbonyl methyl) amino-sulfonyls of N-) benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-dimethylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-cyclopropyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (the methylamino carbonyl methyl) amino-sulfonyls of N-) benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (the methylamino carbonyl methyl) amino-sulfonyls of N-) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(amino carbonyl methyl amino-sulfonyl) benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(3-(N, two (amino carbonyl methyl) amino-sulfonyls of N-) benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2,6-two fluoro-3-dimethylamino Sulphonylbenzyls)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-methyl piperidine base Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-phenylsulfamoyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-morpholinyl Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-methylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-methylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-methyl piperidine base Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-cyclopropyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-tertiary butyl carbonyl diazanyl Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-propionyl group diazanyl Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-chloro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
N-methyl-N-ethyl-carboxylamine 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Morpholine formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Piperidine carboxylic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
N-methyl-N-phenyl-carboxylamine 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Diisopropylaminoethyl formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-chloro-6-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-7-(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)-4-methyl-6-chloro-7-(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,
Dimethylamino formic acid 2-oxo-2H-3-(2,4-two fluoro-3-methylamino-Sulphonylbenzyls)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl isophthalic acid-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-diazanyl Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-fluoro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-hydroxyl-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-hydroxyethylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-dimethyl aminoethyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-tertiary butyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-hydroxyl amino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-dimethylamino carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-morpholinyl carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-7-(to chloropyrimide-2-base oxygen base)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-amino-sulfonyl benzyl)-4-methyl-6-chloro-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-kharophen Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-kharophen Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
3-(4-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl)-4-methyl-6-chloro-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-piperidino carbonyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-morpholinyl carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
3-(4-fluoro-morpholinyl carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-N-METHYL PIPERAZINE base carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-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-methylamino carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
3-(4-fluoro-3-N-methylamino carbonylamino Sulphonylbenzyl)-4-methyl-7-(pyrimidine-2-yloxy)-2-oxo-2H-1-chromene,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-N-methylamino carbonylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-amino-sulfonyl benzyl)-4-hydroxyethyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-hydroxypropyl amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(methoxy ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(methoxy-propyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(morpholinyl ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(N-METHYL PIPERAZINE base ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(piperidyl ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-carboxymethylamino Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-propyloic amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(amino carbonyl methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(methylamino carbonyl methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(N, N-dimethylamino carbonyl methyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(N-methyl piperidine-4-yl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(pyridin-4-yl ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(aminopropyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(amino-ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(azetidine-3-yl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(tetramethyleneimine-3-yl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(piperidin-4-yl ethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(2-fluoro-3-(hydroxyethylamino) Sulphonylbenzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(methyl) (tetramethyleneimine-3-yl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(4-hydroxyl cyclohexyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(methyl) (hydroxyethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(2, the 3-dihydroxypropyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(methylol) (hydroxyethyl) amino-sulfonyl benzyl)-4-methyl-6-chloro-1-chromene-7-base ester,
Dimethylamino formic acid 2-oxo-2H-3-(4-fluoro-3-(1-aminocarboxyl-2-hydroxyethylamino alkylsulfonyl) benzyl)-4-methyl-6-chloro-1-chromene-7-base ester.
5. pharmaceutical composition, it is characterized in that: said pharmaceutical composition comprises each described compound or its pharmacy acceptable salt or solvolyte and pharmaceutically acceptable carrier among claims 1-4.
6. each described compound or its pharmacy acceptable salt or the solvolyte application in the pharmaceutical composition of preparation treatment cell proliferation disorders or inflammatory disease among claims 1-4.
7. application as claimed in claim 6 is characterized in that: said cell proliferation disorders is selected from cancer.
8. application as claimed in claim 7 is characterized in that: said cancer is selected from melanoma, mammary cancer, colorectal carcinoma, carcinoma of the pancreas and lung cancer.
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| CN201210201758.2A CN102827124B (en) | 2011-06-17 | 2012-06-15 | Coumarin derivatives and pharmaceutical composition thereof and purposes |
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| CN201210201758.2A CN102827124B (en) | 2011-06-17 | 2012-06-15 | Coumarin derivatives and pharmaceutical composition thereof and purposes |
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| WO (1) | WO2012171488A1 (en) |
Cited By (3)
| 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 |
| CN110294732A (en) * | 2018-08-17 | 2019-10-01 | 江苏新元素医药科技有限公司 | Medical compounds and its application for treating hepatopathy |
| WO2023143206A1 (en) * | 2022-01-26 | 2023-08-03 | 南京明德新药研发有限公司 | Coumarin compounds and uses thereof |
Citations (3)
| 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 |
| CN101384577A (en) * | 2006-02-09 | 2009-03-11 | 中外制药株式会社 | Novel coumarin derivative having antitumor activity |
| US20110009398A1 (en) * | 2007-07-20 | 2011-01-13 | Toshiyuki Sakai | p27 Protein Inducer |
-
2012
- 2012-06-15 CN CN201210201758.2A patent/CN102827124B/en active Active
- 2012-06-15 WO PCT/CN2012/077019 patent/WO2012171488A1/en active Application Filing
Patent Citations (3)
| 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 |
| CN101384577A (en) * | 2006-02-09 | 2009-03-11 | 中外制药株式会社 | Novel coumarin derivative having antitumor activity |
| US20110009398A1 (en) * | 2007-07-20 | 2011-01-13 | Toshiyuki Sakai | p27 Protein Inducer |
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| Title |
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| JIE-FEI CHENG ET AL.: "Discovery and structure–activity relationship of coumarin derivatives as TNF-α inhibitors", 《BIOORG. MED. CHEM. LETT.》, vol. 14, 31 December 2004 (2004-12-31), pages 2411 - 2415, XP004841211 * |
| SHULIN HAN ET AL.: "Identification of coumarin derivatives as a novel class of allosteric MEK1 inhibitors", 《BIOORG. MED. CHEM. LETT.》, vol. 15, 30 September 2005 (2005-09-30), pages 5467 - 5473 * |
Cited By (3)
| 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 |
| CN110294732A (en) * | 2018-08-17 | 2019-10-01 | 江苏新元素医药科技有限公司 | Medical compounds and its application for treating hepatopathy |
| WO2023143206A1 (en) * | 2022-01-26 | 2023-08-03 | 南京明德新药研发有限公司 | Coumarin compounds and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102827124B (en) | 2015-10-21 |
| WO2012171488A1 (en) | 2012-12-20 |
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