CN106543048A - A kind of new 3 methoxybenzyl benzamides adjusts the compound and its medical usage of estrogen-related receptor activity - Google Patents
A kind of new 3 methoxybenzyl benzamides adjusts the compound and its medical usage of estrogen-related receptor activity Download PDFInfo
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- CN106543048A CN106543048A CN201610859798.4A CN201610859798A CN106543048A CN 106543048 A CN106543048 A CN 106543048A CN 201610859798 A CN201610859798 A CN 201610859798A CN 106543048 A CN106543048 A CN 106543048A
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- compound
- err
- pharmaceutically acceptable
- estrogen
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- XBOKDFZQZMENTD-UHFFFAOYSA-N CC1CC(OC)=CCC1 Chemical compound CC1CC(OC)=CCC1 XBOKDFZQZMENTD-UHFFFAOYSA-N 0.000 description 1
Classifications
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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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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
Abstract
The invention discloses a kind of new 3 methoxybenzyl benzamides with Formulas I adjusts compound and its pharmaceutically acceptable salt and its application of estrogen-related receptor activity.The compound and its pharmaceutically acceptable salt can be used to prepare with regulation estrogen-related receptor ERR alpha(Estrogen related receptor alpha, ERR alpha or ERR α)Activity, prevents and treats the medicine of the malignant tumours such as breast cancer, prostate cancer, cancer of the stomach, colon cancer, oophoroma, cervical carcinoma.
Description
Technical field
The present invention relates to a kind of new 3- methoxybenzyls-benzamide compound and its pharmaceutically acceptable salt conduct
Adjust estrogen-related receptor ERR-alpha(Estrogen-related receptor alpha, ERR-alpha or ERR α)
Conditioning agent and its drug regimen and its prepare prevention and/or treat breast cancer, prostate cancer, cancer of the stomach, colon cancer, oophoroma,
Purposes in the medicine of the tumour such as 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 tumour such as bone flesh, brown fat and breast cancer, oophoroma etc. can be detected.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 ERs ER α, ERR α can not be tied with estrogen
Close, but can be with ER α competition binding estrogen response elements(Estrogen response elemnt, ERE), recognition sequence is
AGGTCAnnn TGACCT;And ERR α also can be reacted with reference to a class I type Steroidgenesis factor with monomer or dimeric form
Element TnAAGGTCA, also referred to as estrogen-related receptor response element(ERR response element, ERRE), show
ERR α and ER α have juxtaposition when DNA is recognized.
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 of the histoorgan that wields influence of its 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
The growth of the breast cancer of bad/non-dependent, invasion and attack, promote vascular smooth muscle cell proliferation, the formation of endothelium micro-pipe and tumor vessel new
It is raw, it is meant that the medicine of targeting ERR α has the effect of anti-breast cancer concurrently, provides New Policy for Molecular Targeted Therapy for Breast Cancer.
In recent years, research disclose the estrogen such as the ERR α breast cancer related to estrogen, carcinoma of endometrium and cervical carcinoma according to
Bad property tumour is closely related, more there are some researches show numerous non-estrogen-dependent tumors such as prostate cancer, sdenocarcinoma of stomach and Colon and rectum
The generation 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,
Express in the tumour such as oophoroma and prostate cancer and significantly raise, be the independent risk factor of a prognosis mala.By raise/under
Adjust ERR alpha expressions or use ERR alpha inhibitors, can effectively suppress the transcriptional activity of hypoxia genes, so as to reduce internal solid tumor
Angiogenesiss with increase.These researchs show that ERR α are probably the potential therapy target of kinds of tumors.ERR α inverse agonists
XCT790 inhibits the propagation and angiogenesis of kinds of tumor cells.ERR α inverse agonists SR16388 effectively inhibit nude mice
The growth of prostate cancer in lotus knurl model.These researchs show that the conditioning agent of targeting ERR α is possible as clinically effective
Antineoplastic.
In sum, 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 acceptor ERR α are developed, it is most likely that become the novel drugs molecule of therapy-related Diseases Tumor.
The content of the invention
1st, it is an object of the invention to provide there is a class estrogen-related receptor ERR-alpha such as following formula I structure to adjust
Section agent or its pharmaceutically acceptable salt.
2nd, a further object of the present invention is the compound or its pharmaceutically acceptable salt for providing Formulas I structure.
3rd, it is still another object of the present invention to provide compound shown in Formulas I or its pharmaceutically acceptable salt are preparing prevention
And/or the application in the medicine for the treatment of tumor disease.Preferably, the tumor disease is breast cancer, prostate cancer, cancer of the stomach, knot
The tumours such as intestinal cancer, oophoroma, cervical carcinoma or carcinoma of endometrium.
4th, a kind of pharmaceutical composition, including the compound of formula I described in the claim 1 of therapeutically effective amount or its pharmaceutically may be used
The salt of acceptance.
5th, it is according to claim 4 to require composition, it is characterized in that, the pharmaceutical composition further containing a kind of or
Various pharmaceutically acceptable carriers or excipient.
6th, pharmaceutical composition according to claim 4, is characterized in that, described compound of formula I or its pharmaceutically may be used
The salt of acceptance accounts for gross weight than 50% ~ 99.5% as active component.
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 biologically active and pharmacology of formula I
Evaluate.
Embodiment 1 tests transcripting regulating activity of the compound of formula I to ERR-alpha using reporter gene
This example illustrates compound of formula I according to the present invention can effectively suppress ERR- in HEKC HEK-293
The expression of the reporter gene regulated and controled by alpha, illustrates that compound of formula I involved in the present invention has effectively regulated and controled ERR-alpha
Function.Reporter gene measuring technology is technology familiar to the staff of this area.
We test compound of formula I to ERRs transcriptional regulatory activities using GAL4 fusion receptors activation method.GAL4 fusions are received
Body activation method is based on mammalian cell single crosses principle, i.e., acceptor LBD and yeast transcription factor DBD to be built into fusion egg
White expression plasmid, makes the LBD of acceptor serve as activation domain (Activation domain, AD).When GAL4 fusion receptors matter
During common with reporter plasmid that GAL4DNA response elements (UAS) the drive transfectional cell of grain, 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
In the presence of, the combination of GAL4 fusion receptors and 5 × UAS is reduced, and will suppress the expression of reporter gene.
In the experiment of the present invention, we by Gal4-ERR-alpha plasmids with express 5 × UAS and to be coupled firefly glimmering
Plasmid (using β-gal expression plasmids as the internal reference) transient cotransfection of light element enzyme reporter gene is thin into mammal HEK-293
The compound of formula I effect 24h of variable concentrations in born of the same parents, is added, the activity change of luciferase and β-gal is detected.
1st, transfect:Inoculation HEK-293 cells in 6cm culture dishes, 6 .0 × 104/ wares, nutrient solution is 10%FBS
DMEM so as to which growth conditions are good.37 DEG C of 5%CO2Culture will be inoculated in 96 holes per the cell in hole 6 × 103 in 24 hours afterwards
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 plus 2mL transfection reagent 3000Transfection Reagent, with hand flick several times, mixing
Room temperature places 5min afterwards.By recombinant plasmid and 3000Transfection Reagent with 1:5 ratio is mixed, and takes 20pmol
Recombinant plasmid (pGal4-ERRs LBD, p5 × UAS-Luc and p β-gal) is added in DMEM, soft to mix.By serum-free
The recombinant plasmid that DMEM has diluted flicks mixing, room with the mixture of the 3000Transfection Reagent of DMEM dilutions again
Temperature places 20min to form the compound of DNA/lipofectamine.By answering for the DNA/lipofectamine being incubated
Compound is added dropwise in the culture dish containing cell and nutrient solution, and gently rocking Tissue Culture Dish back and forth makes cell transfecting
Efficiency is improved, and culture dish is put into 37 DEG C, 5%CO2Cultivate 6 hours in incubator, change fresh medium and (reduce the thin of liposome
Cellular toxicity).Cell is re-digested, is inoculated in 96 hole Costar Tissue Culture Plates with the cell in 1 × 104/ hole.
2nd, compound of formula I and positive drug XCT790 are added:After transfection 8h, addition compound of formula I is in 96 orifice plates.By the positive
Control XCT790 and compound of formula I are diluted to 10 × aimed concn and add 96 hole Costar Tissue Culture Plates, and volume is 10 μ l, after
24 hours each 3 multiple holes of concentration of continuous culture, after cultivating 24 hours, discard nutrient solution in culture plate, add 100 μ of cell pyrolysis liquid
L, respectively take 50 μ l carries out the determination of activity of firefly luciferase and beta galactosidase respectively with MD multi-function microplate readers, with phase
Compound of formula I is calculated to uciferase activity (ratio of firefly luciferase activity/betagalactosidase activity) to ERR-
The transcripting regulating activity of alpha.
Test result indicate that, compound of formula I according to the present invention can dose-dependently suppress the transcriptional activation of ERR α,
( IC50=0.94 ± 0.11 μM), (IC consistent with positive control XCT790 trend50=0 .02 μM of .32 ± 0).
Embodiment described above, description are more concrete and detailed, but therefore can not be interpreted as to patent model of the present invention
The restriction enclosed.It should be pointed out that for the person of ordinary skill of the art, in the premise without departing from present inventive concept
Under, some deformations and improvement can also be made, these belong to protection scope of the present invention.Therefore, the protection of patent of the present invention
Scope should be defined by appended right.
Claims (6)
1. a kind of compound and its pharmaceutically acceptable salt are preparing regulation estrogen-related receptor ERR-alpha
(Estrogen-related receptor alpha, ERR-alpha or ERR α)Purposes in the medicine of conditioning agent, its feature
It is that the compound is 5- [3- (2,5- diethoxy -4- Methanesulfomides-benzyl)-urea groups] -2- ethyoxyl-N- (3- methoxies
Base-benzyl)-benzamide, structural formula is shown in formula I.
2. the purposes according to claim 1, is characterized in that, the pharmaceutically acceptable salt be the compound of formula I with
Salt produced by various inorganic acids, inorganic base, organic acid, organic base reaction.
3. the purposes according to claim 1, is characterized in that, the compound of formula I and its pharmaceutically acceptable salt are in system
In the medicine of standby prevention and/or treatment breast cancer, prostate cancer, cancer of the stomach, colon cancer, oophoroma, cervical carcinoma or carcinoma of endometrium
Purposes.
4. a kind of pharmaceutical composition, including the compound of formula I described in the claim 1 of therapeutically effective amount or which is pharmaceutically acceptable
Salt.
5. it is according to claim 4 to require composition, it is characterized in that, the pharmaceutical composition further contains one or more
Pharmaceutically acceptable carrier or excipient.
6. pharmaceutical composition according to claim 4, is characterized in that, described compound of formula I or which is pharmaceutically acceptable
Salt account for gross weight than 50% ~ 99.5% as active component.
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Citations (4)
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---|---|---|---|---|
US20040259912A1 (en) * | 2001-09-28 | 2004-12-23 | Takahiro Matsumoto | Benzine derivatives, process for preparing the same and use thereof |
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 |
CN105820094A (en) * | 2015-01-05 | 2016-08-03 | 齐鲁工业大学 | 4-methoxy-benzyl-based substituted benzamide new compound, preparation method and application |
-
2016
- 2016-09-28 CN CN201610859798.4A patent/CN106543048B/en not_active Expired - Fee Related
Patent Citations (4)
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 |
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 |
CN105820094A (en) * | 2015-01-05 | 2016-08-03 | 齐鲁工业大学 | 4-methoxy-benzyl-based substituted benzamide new compound, preparation method and application |
Non-Patent Citations (4)
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DU YONGLI等: ""Discovery of novel, potent, selective and cellular active ADC type PTP1B inhibitors via fragment-docking-oriented de novel design"", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
刘红兵: ""蛋白酪氨酸磷酸酶1B调控非小细胞肺癌增殖、转移及机制研究"", 《中国博士学位论文全文数据库,医药卫生科技辑》 * |
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