CN103044325A - Anti-breast cancer application of indeno isoquinoline estrogen receptor alpha regulator - Google Patents
Anti-breast cancer application of indeno isoquinoline estrogen receptor alpha regulator Download PDFInfo
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- CN103044325A CN103044325A CN2012105412901A CN201210541290A CN103044325A CN 103044325 A CN103044325 A CN 103044325A CN 2012105412901 A CN2012105412901 A CN 2012105412901A CN 201210541290 A CN201210541290 A CN 201210541290A CN 103044325 A CN103044325 A CN 103044325A
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- estrogen receptor
- receptor alpha
- breast cancer
- estrogen
- uterus
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Abstract
The present invention relates to an estrogen receptor regulator of a formula (I) or a pharmaceutically acceptable salt thereof. The compounds can combine with the estrogen receptor alpha to produce the anti-breast cancer function and produce regulation function in uterus and other parts at the same time. The compounds have strong function of combining with the estrogen receptor alpha in vitro, and can effectively antagonize the combination of estrogen and the estrogen receptor alpha, thus treating breast cancer caused by excessive estrogen, while playing the role of regulating in the uterus and other parts.
Description
Technical field
The present invention relates to estrogen receptor alpha modulators and the anti-breast cancer effect thereof of a class indenoisoquinoline class, and produce regulating effect at positions such as uterus simultaneously.
Background technology
In recent years, mammary cancer has become the common cancer that ranks the first in the women, and anti-breast cancer medicines research has important science and realistic meaning.
The research discovery, (estrogen receptor, ER) is relevant for the genesis of mammary cancer and estrogen receptor.ER is a kind of nuclear receptor, comprises two kinds of hypotypes of ER α and ER β.The aminoacid sequence of ER α and ER β is respectively 96% and 53% at DNA in conjunction with the homology of territory (DNA binding domain, DBD) and ligand binding domain (ligand binding domain, LBD).Target tissue such as the positions such as uterus, mammary gland in the estradiol effect of classics have a large amount of ER α to distribute, and ER α is low in the positions such as the target tissue of non-classical estradiol effect such as prostate gland, testis, ovary expresses or do not express, and ER β high expression level.In addition, the transcriptional activity of ER α and ER β and also often different from the interaction of cofactor.
ER α is combined rear by expressing in conjunction with the estrogen response element on the target gene (estrogen response element, ERE) regulatory gene or interacting to change the transcriptional activity of gene with other nucleoprotein with oestrogenic hormon.
Many evidences show that ER α is a very attractive anti-breast cancer treatment target.The long-term overstimulation of oestrogenic hormon, ER alpha expression level increase or the transcriptional activation activity enhancing is an important factor that causes mammary cancer.The ER that at first exists in the mammary cancer mainly is ER α, and when normal galactophore tissue became tumorigen, the level of ER α increased and the reduction of ER β level.The second, mammary cancer is as a kind of hormone-dependent tumor, and its growth and transfer are subjected to estrogen regulating, and oestrogenic hormon can be transcribed the expression of raising the promoting growth of cell gene by its receptor activation.The mechanism that the conditioning agent of ER α can be regulated estrogen effect be with oestrogenic hormon competition bind receptor on LBD, be combined with ER α and form the dimer mixture, change the conformation of ER α, thereby the AF2 district of the blocking-up co-activation factor and ER α interacts, the growth-promoting effect of ER α in breast cancer cell of blocking-up oestrogenic hormon combination.
At present a lot of companies, scientific research institution have all carried out the research for the ER alpha modulators, and increasing to the Research Literature of the Molecular biological function of ER, Patents also constantly occurs.Tamoxifen (Tamoxifen) is first targeting cancer therapy medicine, is used for the treatment of mammary cancer, and the approvals as selective estrogen receptor modulators acquisition FDA in 1977 are used for the treatment of postmenopausal women with advanced mammary cancer.But it has hormesis to uterine cell, and life-time service easily causes endometrial hyperplasia or carcinoma of endometrium, can also cause the side effects such as vasorelaxation, phlebothrombosis in addition.1997 New Year's gifts come the raloxifene acquisition FDA approval of company to be used for the treatment of osteoporosis, and FDA had ratified its New indication in 2007, for reducing the mammary cancer risk of postmenopausal osteoporosis female patient.But being warned, raloxifene can increase palsy associated death risk.Raloxifene is s-generation selective estrogen receptor modulators, can Breast Cancer Prevention and do not increase and suffer from the carcinoma of endometrium risk.Toremifene is the analog of tamoxifen, is approved for the treatment infiltrative breast carcinoma in countries such as the U.S. at present, than tamoxifen less potential tool Genotoxic Effect is arranged, and causes that the risk of Secondary cases carcinoma of endometrium is less than tamoxifen.Owing to can significantly reduce the incidence of postmenopausal osteoporosis fracture and coronary heart disease during the diseases such as controversies in hormone replacement in the elderly treatment involution syndrome, osteoporosis, senile dementia and cardiovascular systems, but may bring out mammary cancer and carcinoma of endometrium; Take the sexual hormoue alternative medicine female, that progestogen is united use for the untoward reaction that overcomes the oestrogenic hormon carcinogenesis and still may increase the incidence of mammary cancer, the generation of the carcinoma of endometrium that can also cause, these untoward reactions impel people to seek a kind ofly uterus and mammary gland are shown estrogenic antagonist and bone ilium and cardiovascular systems to be had the medicine of estrogen-like effects.Therefore the ER alpha modulators of Effect of Anti mammary cancer effect is the important foundation of research selective estrogen receptor modulators.
Summary of the invention
The object of the invention is to develop the application of oestrogen-like hormone receptor alpha modulators in breast cancer treatment.The compound of the present invention screening be a collection of orientation synthetic can be in conjunction with the compound of ER α target spot, the high flux screening model that utilizes the fluorescence polarization method to set up carries out in-vitro screening to this batch compound, seek lead compound and drug candidate by functional checking, simultaneously screening gained active compound is carried out Pharmacodynamic and Mechanism Study, find the ER alpha modulators of a class indenoisoquinoline class formation, for the anti-breast cancer treatment provides drug candidate, and produce regulating effect at positions such as uterus simultaneously.This compounds is synthetic by China Medicine University experimental teaching of medicinal chemistry chamber, wherein testing compound 001672 and 001626 synthetic method can be from patents to China, Wang Tianlin, Xiao Hong, You Qidong, Yao Yao, Li Xiaobo, Liao Qingjiang. the indenoisoquinoline ketone derivatives, its preparation method and medicinal use .ZL 20,091 0233991.7 and Hua Xiang, Tianlin Wang, Hong Xiao, Qidong You, Yao Yao, Xiaobo Li, QingjiangLiao.Indenoisoquinolinone derivatives obtains among the manufacturing method and medical use thereof.WO2011047515A1..
Technical scheme of the present invention is: set up ER α receptor target regulator screening model, and primary dcreening operation, multiple sieve, the structure activity relationship analysis obtains the drug candidate that a class has the anti-breast cancer effect.Concrete steps are as follows:
Step 1: set up ER alpha modulators high flux screening model.
Step 2: by the positive drug verification model.
Step 3: use ER alpha modulators high flux screening model that testing compound is carried out primary dcreening operation, multiple sieve, draw testing compound antagonism estradiol and ER α binding curve and measure IC
50Value.
The invention provides the medical use of above-claimed cpd or its pharmaceutically-acceptable salts and medicinal compositions thereof, especially the purposes in the disease, particularly anti-breast cancer medicines of preventing, delay or treating ER α participation mediation.The synthetic effect of compound in breast cancer treatment of above-mentioned orientation belongs to protection scope of the present invention.
Description of drawings:
Fig. 1: the inhibition graphic representation that positive drug 4-OH-Tamoxifen antagonism estradiol is combined with ER α.
Fig. 2: the inhibition graphic representation that testing compound 001672 antagonism estradiol is combined with ER α.
Fig. 3: the inhibition graphic representation that testing compound 001626 antagonism estradiol is combined with ER α.
Fig. 4: the inhibition graphic representation that testing compound 000394 antagonism estradiol is combined with ER α.
Fig. 5: the inhibition graphic representation that testing compound 000356 antagonism estradiol is combined with ER α.
Embodiment
Below in conjunction with description of drawings the specific embodiment of the present invention:
1. testing compound antagonism estradiol is combined active testing with ER α
1) experiment material
Estrogen Receptor-alpha (ER α) Human Recombinant (Invitrogen, USA), FluormoneTMES2 (Invitrogen, USA), ES2Screening Buffer (Invitrogen, USA), Estradiol preserves standard substance for this chamber, the standard substance that domestic analytical pure, Tamoxifen provide for China Medicine University experimental teaching of medicinal chemistry chamber, 384 hole black microwell plate (Corning, USA), rifle head (Axygen, USA).
2) experimental procedure
● every kind of accurate weighing of testing compound, add the DMSO solvent and become mother liquor, then use ES2Screening Buffer preparation testing compound solution to desired concn, primary dcreening operation concentration is about 1 * 10
-3Mol/L.
● solution preparation 2X Fluormone
TMES2/ER α Complex: use ES2Screening Buffer preparation 2XFluormone
TMIt is 9nM that ES2 and ER α mixed solution make final FluormoneTM ES2 concentration, and ER α concentration is 30nM.
● being at war with property is in conjunction with experiment: add 50 μ l compounds in the every hole of black microwell plate, 384 hole first, every hole adds 50ul 2XFluormone again
TMES2 and ER α mixing solutions.Add simultaneously 50 μ l estradiol solution (1nM), 50 μ l 2X Fluornone
TMES2 and ER α mixing solutions are as 100% competition combination contrast, adding 50 μ l Buffer, 50 μ l 2X Fluormone
TMES2 and ER α mixing solutions are as 0% competition combination contrast and add 100 μ l Buffer as blank.The lucifuge operation.Room temperature (20-25 ℃) is hatched 90min.
● microplate reader reads every hole polarization value.
2. data processing
1) calculates the inhibiting rate that positive drug and testing compound antagonism estradiol are combined with ER α according to formula
2) draw positive drug 4-OH-Tamoxifen antagonism estradiol and ER α binding curve and measure IC
50Value is seen Fig. 1.
3) use milli partially value and the mapping of logarithm concentration value, draw testing compound antagonism estradiol and ER α binding curve and measure IC
50Value is seen Fig. 2-5.
Sieve again experimental result
External estrogen receptor alpha modulators screening model records the IC of positive drug 4-OH-Tamoxifen
50Be 0.34nM, the compound that screening obtains can be summarized as according to the structure of parent nucleus a class, structural formula and external estrogen receptor alpha screening active ingredients IC
50As follows:
1:5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydro-pyrazole be [1,5a] pyrimidine also
Claims (3)
1. following formula: compound or its acceptable salt pharmaceutically:
Wherein:
R
1, R
2Independently represent separately H ,-OH, C
1-C
4Alkoxyl group or C
1-C
6Carbalkoxy;
R
3, R
4Independently represent separately CO (CH
2)
2CH
3, CO (CH
2)
3CH
3Or C1-C
6Alkyl; Or R
3And R
4And coupled nitrogen-atoms is combined into piperidyl, pipecoline base, homopiperidinyl, morpholinyl, pyrrolidyl, 3-methylpyrrole alkyl, 3,3-alkyl dimethyl pyrrole, 3,4-alkyl dimethyl pyrrole, piperazinyl, N methyl piperazine base, NEP base, N-Phenylpiperazinyl or N-benzyl piperazine base;
X represents O, S, NH, CH
2Or-CO-;
M=0 or 1;
N=2 or 3.
The compound of the claimed formula (I) of claim 1 or its pharmaceutically acceptable salt and produce simultaneously regulating effect at positions such as uterus for the preparation of the purposes of estrogen receptor alpha modulators.
3. according to the purposes of claim 2, as estrogen receptor alpha modulators, be used for the treatment of mammary cancer, and produce regulating effect at positions such as uterus simultaneously.
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| CN2012105412901A CN103044325A (en) | 2012-12-12 | 2012-12-12 | Anti-breast cancer application of indeno isoquinoline estrogen receptor alpha regulator |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109748870A (en) * | 2017-11-08 | 2019-05-14 | 姚清发 | The preparation method of indenoisoquinoline derivative |
| CN111067907A (en) * | 2018-10-18 | 2020-04-28 | 常州大学 | Application of progestogen in inhibiting vascular endothelial growth factor expression |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007059008A2 (en) * | 2005-11-14 | 2007-05-24 | Purdue Research Foundation | N-substituted indenoisoquinolines and syntheses thereof |
| CN101565402A (en) * | 2009-05-19 | 2009-10-28 | 中国药科大学 | Indeno isoquinolone compound and preparation method and medical application thereof |
| CN101693688A (en) * | 2009-10-22 | 2010-04-14 | 中国药科大学 | Indeno isoquinolone derivatives, preparation process and medical application thereof |
-
2012
- 2012-12-12 CN CN2012105412901A patent/CN103044325A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007059008A2 (en) * | 2005-11-14 | 2007-05-24 | Purdue Research Foundation | N-substituted indenoisoquinolines and syntheses thereof |
| CN101565402A (en) * | 2009-05-19 | 2009-10-28 | 中国药科大学 | Indeno isoquinolone compound and preparation method and medical application thereof |
| CN101693688A (en) * | 2009-10-22 | 2010-04-14 | 中国药科大学 | Indeno isoquinolone derivatives, preparation process and medical application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 王天麟 等: "新型6-芳基茚并异喹啉酮衍生物的合成及抗肿瘤活性研究", 《中国药物化学杂志》 * |
| 马兴丽: "***、***受体与乳腺癌", 《中国医药指南》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109748870A (en) * | 2017-11-08 | 2019-05-14 | 姚清发 | The preparation method of indenoisoquinoline derivative |
| CN109748870B (en) * | 2017-11-08 | 2021-02-12 | 姚清发 | Process for preparing indenoisoquinoline derivatives |
| CN111067907A (en) * | 2018-10-18 | 2020-04-28 | 常州大学 | Application of progestogen in inhibiting vascular endothelial growth factor expression |
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Application publication date: 20130417 |