CN106543047B - A kind of p- tolyls of new N--benzamides adjusts the compound and its medical usage of estrogen-related receptor activity - Google Patents
A kind of p- tolyls of new N--benzamides adjusts the compound and its medical usage of estrogen-related receptor activity Download PDFInfo
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- CN106543047B CN106543047B CN201610858291.7A CN201610858291A CN106543047B CN 106543047 B CN106543047 B CN 106543047B CN 201610858291 A CN201610858291 A CN 201610858291A CN 106543047 B CN106543047 B CN 106543047B
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- estrogen
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- related receptor
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the compound and its pharmaceutically acceptable salt of a kind of new N p-methylphenyls benzamides adjusting estrogen-related receptor activity with Formulas I and its applications.The compound and its pharmaceutically acceptable salt, which can be used for preparing having, adjusts estrogen-related receptor ERR alpha（Estrogen related receptor alpha, ERR alpha or ERR α）Activity, the drug of the malignant tumours such as prevention and treatment breast cancer, prostate cancer, stomach cancer, colon cancer, oophoroma, cervical carcinoma.
Description
Technical field
The present invention relates to a kind of p- tolyl-benzamide compounds of new N- and its pharmaceutically acceptable salt to make
To adjust estrogen-related receptor ERR-alpha（Estrogen-related receptor alpha, ERR-alpha or ERR
α）Conditioning agent and its pharmaceutical composition and its prepare prevention and/or treatment breast cancer, prostate cancer, stomach cancer, colon cancer, ovary
Purposes in the drug of the tumours such as cancer, cervical carcinoma or carcinoma of endometrium.
Background technology
ERR α are in 1988 by clone identifications such as Giguere.As orphan nuclear receptor（Orphan nuclear
receptor）, ERR α endogenic ligands are undiscovered always.ERR α wide expressions in vivo, from cardiac muscle, alimentary canal, brain, bone
Malignant tumours such as bone flesh, brown fat and breast cancer, oophoroma etc. can detect.ERR α and estrogen receptor alpha（ERα）Have
Higher homology：DNA binding domain（DNA binding domain, DBD）Amino acid similarity 68%, ligand binding domain
（Ligand binding domain, LBD）Similitude 33%.Different from estrogen receptor ER α, ERR α cannot be with estrogen knot
It closes, but can be with ER α competitive binding estrogen response elements（Estrogen response elemnt, ERE）, identify that sequence is
AGGTCAnnn TGACCT；And ERR α can also combine the reaction of one kind I type Steroidgenesis factor in the form of monomer or dimer
Element TnAAGGTCA, also referred to as estrogen-related receptor response element（ERR response element, ERRE）, show
ERR α and ER α have juxtaposition when identifying DNA.
Nearest research prompting, except participating in ER signal paths, ERR α are in cellular energy metabolism, mitochondrial oxidation and biology
Synthesis etc. has an important physiological action, the development for the histoorgan that wields influence of function, the aging of cell, the generation of tumour and
Development etc..
Oncobiology basic research shows orphan nuclear receptor-estrogen-related receptor α（ERRα）Can promote hormone according to
Growth, the invasion and attack of bad/non-dependent breast cancer promote vascular smooth muscle cell proliferation, the formation of endothelium micro-pipe and tumor vessel new
It is raw, it is meant that the drug of targeting ERR α has both the effect of anti-breast cancer, and new strategy is provided for Molecular Targeted Therapy for Breast Cancer.
In recent years, research disclose the estrogen such as ERR α and the relevant breast cancer of estrogen, carcinoma of endometrium and cervical carcinoma according to
Bad property tumour is closely related, and more some researches show that numerous non-estrogen dependent tumors such as prostate cancer, sdenocarcinoma of stomach and Colon and rectums
The occurrence and development of cancer etc. and clinical prognosis are also related to the expression of ERR α.Clinical research confirmation, ERR α breast cancer, colon cancer,
Significantly up-regulation is expressed in the tumours such as oophoroma and prostate cancer, is the independent risk factor of a prognosis mala.By up-regulation/under
It adjusts ERR alpha expressions or uses ERR alpha inhibitors, can effectively inhibit the transcriptional activity of hypoxia genes, so as to reduce internal solid tumor
Angiogenesis and growth.These researchs show that ERR α may be the potential therapy target of kinds of tumors.ERR α inverse agonists
XCT790 inhibits the multiplication and angiogenesis of kinds of tumor cells.ERR α inverse agonists SR16388 effectively inhibits nude mice
The growth of prostate cancer in lotus knurl model.These researchs show to target the conditioning agent of ERR α possible as clinically effective
Antitumor drug.
In conclusion estrogen-related receptor ERR α can be as the novel therapeutic target spot of kinds of tumors, based on estrogen phase
Close the small-molecule modulators that receptor ERR α are developed, it is most likely that as the novel drugs molecule for the treatment of relevant disease tumour.
The content of the invention
1st, it is an object of the invention to provide a kind of estrogen-related receptor ERR-alpha tune having such as following formula I structure
Save agent or its pharmaceutically acceptable salt.
2nd, another object of the present invention is to provide the compound of Formulas I structure or its pharmaceutically acceptable salt.
3rd, it is still another object of the present invention to provide compounds shown in Formulas I or its pharmaceutically acceptable salt to prepare prevention
And/or the application in the drug for the treatment of tumor disease.Preferably, the tumor disease is breast cancer, prostate cancer, stomach cancer, knot
The tumours such as intestinal cancer, oophoroma, cervical carcinoma or carcinoma of endometrium.
4th, a kind of pharmaceutical composition, compound of formula I described in claim 1 including therapeutically effective amount or its pharmaceutically may be used
The salt of receiving.
5th, it is according to claim 4 to require composition, it is characterized in that, the pharmaceutical composition further containing a kind of or
A variety of pharmaceutically acceptable carriers or excipient.
6th, pharmaceutical composition according to claim 4, it is characterized in that, the compound of formula I or its pharmaceutically may be used
The salt of receiving accounts for total weight than 50% ~ 99.5% as active ingredient.
Specific embodiment
The present invention is described in more detail below by specific embodiment, to be better understood from the present invention, but
Following embodiments are not intended to limit the scope of the invention, will be detailed below the bioactivity and pharmacology of formula Compound I
Evaluation.
Implementation column 1 is using reporter gene test compound of formula I to the transcripting regulating activity of ERR-alpha
This example illustrates compound of formula I of the present invention can effectively inhibit in human embryonic kidney cells HEK-293
The expression for the reporter gene that ERR-alpha is regulated and controled illustrates that compound of formula I according to the present invention has effectively regulated and controled ERR-
The function of alpha.Reporter gene measuring technology is technology known to the staff of this field.
We test compound of formula I to ERRs transcriptional regulatory activities using GAL4 fusion receptors activation method.GAL4 fusion by
Body activation method is based on mammalian cell single crosses principle, i.e., receptor LBD with yeast transcription factor DBD is built into and merges egg
White expression plasmid makes the LBD of receptor serve as activation domain (Activation domain, AD).When GAL4 fusion receptors matter
During the common transfectional cell of reporter plasmid that grain drives with GAL4DNA response elements (UAS), in the effect of receptor stimulating agent
Under, GAL4 fusion receptors are incorporated on 5 × UAS, drive the expression of reporter gene.And in receptor inverse agonists or antagonist
Under the action of, the combination of GAL4 fusion receptors and 5 × UAS are reduced, and will inhibit the expression of reporter gene.
In the experiment of the present invention, we are by Gal4-ERR-alpha plasmids with expressing 5 × UAS and to be coupled firefly glimmering
It is thin that plasmid (using β-gal expression plasmids as internal reference) transient cotransfection of light element enzyme reporter gene enters mammal HEK-293
In born of the same parents, the compound of formula I effect for adding in various concentration detects luciferase and the activity change of β-gal for 24 hours.
1st, transfect：HEK-293 cells are inoculated in 6cm culture dishes, the ware of 6 .0 × 104/, culture solution 10%FBS
DMEM makes its growth in good condition.37 DEG C of 5%CO2Cultivate 24 it is small when after, by per hole 6 × 103 cell inoculation in 96 holes
Costar Tissue Culture Plates, overnight incubation.When cell density reaches 70%, take the serum-free medium (DMEM) of 50mL in
In the centrifuge tube of 1.5mL, then add the transfection reagent 3000Transfection Reagent of 2mL, flicked several times with hand, mixing
5min is placed at room temperature for afterwards.By recombinant plasmid and 3000Transfection Reagent with 1:5 ratio mixing, takes 20pmol
Recombinant plasmid (pGal4-ERRs LBD, p5 × UAS-Luc and p β-gal) is added in DMEM, soft to mix.By serum-free
Mixture of the recombinant plasmid that DMEM has diluted again with the diluted 3000Transfection Reagent of DMEM flicks mixing, room
Temperature places 20min to form the compound of DNA/lipofectamine.By answering for the DNA/lipofectamine being incubated
It closes object to be added dropwise in the culture dish containing cell and culture solution, gently rocking Tissue Culture Dish back and forth makes cell transfecting
Efficiency improves, and culture dish is put into 37 DEG C, 5%CO2When culture 6 is small in incubator, changes fresh medium and (reduce the thin of liposome
Cellular toxicity).Cell is re-digested, with the cell inoculation in 1 × 104/ hole in 96 hole Costar Tissue Culture Plates.
2nd, compound of formula I and positive drug XCT790 are added in：After transfecting 8h, compound of formula I is added in into 96 orifice plates.By the positive
Control XCT790 and compound of formula I are diluted to 10 × aimed concn and add in 96 hole Costar Tissue Culture Plates, and volume is 10 μ l, after
Each 3 multiple holes of concentration when continuous culture 24 is small, when culture 24 is small after, discard culture solution in culture plate, add in 100 μ of cell pyrolysis liquid
L respectively takes 50 μ l to carry out the determination of activity of firefly luciferase and beta galactosidase with MD multi-function microplate readers respectively, with phase
Compound of formula I is calculated uciferase activity (ratio of firefly luciferase activity/betagalactosidase activity) to ERR-
The transcripting regulating activity of alpha.
The experimental results showed that compound of formula I of the present invention can dose-dependently inhibit the transcriptional activation of ERR α,
(IC50=3.04 ± 0.16 μM), (IC consistent with positive control XCT790 trend50=0.32 ± 0 .02 μM).
Embodiment described above, description is more specific and detailed, but can not therefore be interpreted as to patent model of the present invention
The limitation enclosed.It should be pointed out that for those of ordinary skill in the art, the premise of present inventive concept is not being departed from
Under, various modifications and improvements can be made, these belong to protection scope of the present invention.Therefore, the protection of patent of the present invention
Scope should be subject to appended right.
Claims (3)
1. a kind of compound and its pharmaceutically acceptable salt are preparing adjusting estrogen-related receptor ERR-alpha
（Estrogen-related receptor alpha, ERR-alpha or ERR α）Purposes in the drug of conditioning agent, feature
Be, the compound for 5- [3- (2,5- diethoxy -4- Methanesulfomides-benzyl)-urea groups] -2- ethyoxyl-N-4- tolyls -
Benzamide, structural formula is shown in formula I
。
2. the purposes according to claim 1, it is characterized in that, the pharmaceutically acceptable salt be the compound of formula I with
Various inorganic acids, inorganic base, organic acid, organic base reaction caused by salt.
3. the purposes according to claim 1, it is characterized in that, the compound of formula I and its pharmaceutically acceptable salt are being made
In the standby drug for preventing and/or treating breast cancer, prostate cancer, stomach cancer, colon cancer, oophoroma, cervical carcinoma or carcinoma of endometrium
Purposes.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610858291.7A CN106543047B (en) | 2016-09-28 | 2016-09-28 | A kind of p- tolyls of new N--benzamides adjusts the compound and its medical usage of estrogen-related receptor activity |
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| CN201610858291.7A CN106543047B (en) | 2016-09-28 | 2016-09-28 | A kind of p- tolyls of new N--benzamides adjusts the compound and its medical usage of estrogen-related receptor activity |
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| CN106543047A CN106543047A (en) | 2017-03-29 |
| CN106543047B true CN106543047B (en) | 2018-05-22 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101142174A (en) * | 2005-03-19 | 2008-03-12 | 株式会社Amorepacific | Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist, and pharmaceutical compositions containing the same |
| WO2010146236A1 (en) * | 2009-06-16 | 2010-12-23 | Biotie Therapies Corp. | Urea substituted sulphonamide derivatives |
| CN105820087A (en) * | 2015-01-05 | 2016-08-03 | 齐鲁工业大学 | 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-p-methylphenyl-benzamide new compound and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040259912A1 (en) * | 2001-09-28 | 2004-12-23 | Takahiro Matsumoto | Benzine derivatives, process for preparing the same and use thereof |
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2016
- 2016-09-28 CN CN201610858291.7A patent/CN106543047B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101142174A (en) * | 2005-03-19 | 2008-03-12 | 株式会社Amorepacific | Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist, and pharmaceutical compositions containing the same |
| WO2010146236A1 (en) * | 2009-06-16 | 2010-12-23 | Biotie Therapies Corp. | Urea substituted sulphonamide derivatives |
| CN105820087A (en) * | 2015-01-05 | 2016-08-03 | 齐鲁工业大学 | 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-p-methylphenyl-benzamide new compound and preparation method and application thereof |
Non-Patent Citations (4)
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| "Discovery of novel, potent, selective and cellular active ADC type PTP1B inhibitors via fragment-docking-oriented de novel design";Du Yongli等;《Bioorganic & Medicinal Chemistry》;20150609;第23卷;第4891-4898页 * |
| "PTP1B在ER阳性乳腺癌中的表达及临床预后意义";赵瑞君等;《临床与实验病理学杂志》;20160520(第5期);第492-495页 * |
| "PTP1B在胃癌组织中表达及其对胃癌细胞系MKN28增殖、侵袭行为的影响";叶亚峻等;《交通医学》;20140420;第28卷(第2期);第111-114页 * |
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