CN102477033A - Benzothiophene compound and application thereof in preventive and/or treatment medicine for breast cancer and osteoporosis - Google Patents

Benzothiophene compound and application thereof in preventive and/or treatment medicine for breast cancer and osteoporosis Download PDF

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CN102477033A
CN102477033A CN2010105545711A CN201010554571A CN102477033A CN 102477033 A CN102477033 A CN 102477033A CN 2010105545711 A CN2010105545711 A CN 2010105545711A CN 201010554571 A CN201010554571 A CN 201010554571A CN 102477033 A CN102477033 A CN 102477033A
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ococ
compound
osteoporosis
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殷建明
朱惠霖
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SUZHOU BORUI PARMACEUTICALS Inc
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SUZHOU BORUI PARMACEUTICALS Inc
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Abstract

The invention relates to a novel benzothiophene derivative and application thereof in preventive and/or treatment medicine for breast cancer and osteoporosis. The benzothiophene derivative is an ideal selective estrogen receptor modulator, can be used for treating or preventing various indications related to estrogen functions, and is particularly applicable to treating post-menopause breast cancer and osteoporosis. The compound has the advantages that oxidative metabolism is lowered, effective bioavailability is higher, and accordingly, dosage of the compound is little, tolerance of the compound is fine, and side effects are low.

Description

Benzo thiophene phenolic cpd and prevent and/or treat the purposes in the mammary cancer osteoporosis agents in preparation
Technical field
The present invention relates to benzo thiophene phenolic cpd and they prevent and/or treat the purposes in the mammary cancer osteoporosis agents in preparation.
Background technology
Selective estrogen receptor modulators (selective estrogen receptor modulators; SERMs) be meant and interact with ERs; Produce the different compound of a series of structures of specific action according to the different of environment in target tissue and the hormone, they show as the effect of quasi-estrin appearance and show as the effect of estrogen antagonist appearance at other tissues at some tissues.Bone and cardiovascular systems are had estrogen-like effects, and breast and uterus are had the effect of estrogen antagonist appearance, and the selective estrogen receptor modulators of spinoffs such as ametria endometrial carcinomas, vascular complication is simultaneously expected.
At present, in clinical trial or the selective estrogen receptor modulators of clinical use mainly contain triphenylethylene analog derivative (Triphenylethylene), benzothiophene derivative (Benzothiophene), benzo pyran derivative (Benzopyrans) and other types Theelin,dihydro-analog derivative.Wherein, Grantedly be applied to clinical selective estrogen receptor modulators and comprise tamoxifen (Tamoxifen) and toremifene (Toremifene) that is used to treat breast cancer and the raloxifene (Raloxifene) that is used for osteoporosis, wherein raloxifene is the representative of benzothiophene derivative.
(estrogen receptor ER) belongs to steroid hormone family nuclear receptor to ERs, is distributed widely in urogenital system, cardiovascular systems, osseous tissue, cns, kidney, prostate gland, lungs and uterus etc.Selective estrogen receptor modulators is brought into play its pharmacological action through the mediation of ER; Be selective estrogen receptor modulators as estrogen agonist or antagonist and cause the ERs conformational change, thus activation or inhibition that the change of this conformation finally causes the oestrogenic hormon target gene to be transcribed.
Mammary cancer is the common a kind of frequently-occurring disease of women.According to investigations, in the annual newly-increased case 180000 of the U.S., death cases in 2000 greater than 40000.The research proof, oestrogenic hormon has been played the part of important role in the mammary cancer pathogenesis.Under the normal circumstances, oestrogenic hormon CE acceptor, the transcribing of activation target gene.But improper or over-drastic oestrogenic hormon token stimulus can cause the generation of cancer.An oestrogenic hormon vital role in vivo is exactly to keep the integrity of bone and bone.Climacteric, the women caused bone to run off fast owing to lacking oestrogenic hormon, caused the imbalance of bone forming and bone resorption thus, increased the risk of fracture.Hormone replacement therapy (HRT) is a kind of traditional means of preventing osteoporosis disease, yet because fear to suffer from mammary cancer, expectation is selected to prevent and treat osteoporosis with a kind of non-Alora.A kind of just ability of raloxifene satisfies the non-steroidal selective estrogen receptor modulators that requires like this.Because raloxifene has the effect of quasi-estrin appearance to bone, and can not increase the ill risk of breast cancer or carcinoma of endometrium, raloxifene has been used for clinical prevention and treatment osteoporosis.
In vitro study proves that raloxifene can suppress oestrogenic hormon competitively and combine with ERs, and people's mammary gland MCF-7 clone ERs dependency proliferative effect is suppressed.The people causes in the rodent model of mammary cancer, has also embodied the estrogenic antagonist of raloxifene, and raloxifene can be blocked the uterus fully to estrogenic reaction.The experiment of spay mouse shows that raloxifene has the bone provide protection, and ability reducing cholesterol level, and the uterus is not had influence.In addition, find in the rabbit experiment of after spay, feeding that raloxifene ability reducing cholesterol is accumulated the active gland, and can suppress the oxidising process of LDL with SUV.
Raloxifene has good tolerability usually, but certain adverse side effect is also arranged, as increases dark venous thrombosis disease, pulmonary infarction disease, the deadly danger that reaches main crown incident of apoplexy.The common untoward reaction of raloxifene is flush, lower limb muscles spasm.All these untoward reactions all dosage with raloxifene are relevant.There is very significantly first pass effect in raloxifene after oral, and absolute bioavailability has only about 2%, and therefore, its using dosage is generally bigger, has increased spinoff to a certain extent and has added heavy patient's treatment cost.Use 14The raloxifene clinical study that C indicates shows; Raloxifene has experienced first pass metabolism more completely; Main metabolites is the glucoside acid conjugate, comprises raloxifene-4 '-glucosiduronate, raloxifene-6-glucosiduronate and raloxifene-6,4 '-diglucuronide.In addition, the water solubility of raloxifene is very low, has only 2ug/ml.This has influence on the formulation preparation and the bioavailability thereof of raloxifene to a great extent.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiency of raloxifene in prevention and the treatment indication relevant with estrogen function, and a kind of improved benzo thiophene phenolic cpd is provided.
The present invention also will provide above-mentioned improved benzo thiophene phenolic cpd to prevent and/or treat osteoporosis in preparation, improve the application in the medicine of female dimacteric syndrome relative disease as selective estrogen receptor modulators simultaneously.
For solving above technical problem, the present invention takes following technical scheme:
Formula I compound and pharmacologically acceptable salt thereof,
Figure BSA00000355547400031
In the said formula I:
R 01, R 02, R 03, R 04, R 05, R 06, R 07, R 08, R 09, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R 24, R 25Be hydrogen or deuterium independently;
R XAnd R YIndependently for being selected from a kind of in the following groups:
H；
COC nH 2n+1；
COC nH 2nNH 2；
COC nH 2nNHC nH 2n+1；
COC nH 2nN(C nH 2n+1)C mH 2m+1；
COC nH 2nN(COC nH 2n+1)C mH 2m+1；
CON(C nH 2n+1)C nH 2nCOOH；
CH 2OCOC nH 2nNH 2；
CH 2OCOC nH 2nNHC nH 2n+1；
CH 2OCOC nH 2nN(C nH 2n+1)C mH 2m+1；
CH 2OCOC nH 2nN(COC nH 2n+1)C mH 2m+1；
CH(CH 3)OCOC nH 2nNH 2；
CH(CH 3)OCOC nH 2nNHC nH 2n+1；
CH(CH 3)OCOC nH 2nNHCOC nH 2n+1；
CH 2OP(OH) 3；
CH(CH 3)OP(OH) 3；
CONC nH 2n+1CH(R AA)COOH；
CH 2OCOCH(R AA)NHC nH 2n+1；
CH 2OCOCH(R AA)NHCOC nH 2n+1；
CH(CH 3)OCOCH(R AA)NHC nH 2n+1；
COCH(R AA)NHC nH 2n+1；
COCH(R AA)NHCOC nH 2n+1；
COCH(R AA)N(C nH 2n+1)C mH 2m+1；
COCH(R AA)N(COC nH 2n+1)C mH 2m+1；
Figure BSA00000355547400041
And
Figure BSA00000355547400042
In the above-mentioned chemical formula, R AAThe amino acid side chain of expression dietary protein origin and/or non-dietary protein origin;
R MExpression OH, OC nH 2n+1, OCOC nH 2n+1, NH 2, NH (C nH 2n+1), N (C nH 2n+1) 2, SH, SC nH 2n+1, SCOC nH 2n+1, CN, F, Cl, Br or I;
N, m are the integer between 1～6 independently,
R XAnd R YBe not H simultaneously.
The preparation of The compounds of this invention can be through the route of synthesis of well-known those the similar methods of chemical field, the synthetic compound of the present invention of description that particularly comprises according to this paper.Reagent generally obtains or is easy to use the well-known method preparation of those skilled in the art from commercial source.According to the present invention, described pharmacologically acceptable salt includes but not limited to hydrochloride, phosphoric acid salt, vitriol, acetate, PHENRAMINE MALEATE, benzene sulfonate, toluenesulfonate, fumarate, tartrate etc.Should be understood that " compound " comprises any kind or all in this type form.
The compounds of this invention is the part of ERs; Therefore can be used for treating or prevent the various indications relevant with estrogen function; Include but not limited to: bone loss, fracture, osteoporosis, cartilage sex change, endometriosis, uterus fiber disease, hot flush, LDL cholesterol levels increase, cardiovascular disorder, recognizing ability infringement, brain degenerative disease, restenosis, gynaecomastia, vascular smooth muscle cell proliferation, obesity, incontinence; And cancer, especially mammary cancer, uterus carcinoma and prostate cancer.Yet the present invention relates generally to its medicinal application in the mammary cancer osteoporosis after treatment menopause.
According to the present invention, n is preferably 2 or 3.
The compound of representational compound of the present invention such as formula II～(VIII) expression.
Figure BSA00000355547400051
Above-mentioned R AAThe amino acid side chain of expression dietary protein origin and/or non-dietary protein origin, for example L-L-Ala side chain.
Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
Compound first pass effect of the present invention reduces; Effectively bioavailability is high; It is as selective estrogen receptor modulators; Can be used for treating or prevent the various indications relevant with estrogen function, it is few to have using dosage when particularly it is used to treat after the menopause mammary cancer osteoporosis, the advantage that spinoff is little.
Embodiment
Below in conjunction with specific embodiment the present invention is done further detailed explanation, but the present invention is not limited to following examples.
Embodiment 1
The compound that present embodiment provides a kind of formula II to represent:
Figure BSA00000355547400061
Embodiment 2
The compound that present embodiment provides a kind of formula III to represent:
Figure BSA00000355547400062
Embodiment 3
The compound that present embodiment provides a kind of formula IV to represent:
Figure BSA00000355547400071
Embodiment 4
Present embodiment provides the compound of a kind of formula (V) expression:
Figure BSA00000355547400072
Embodiment 5
The compound that present embodiment provides a kind of formula VI to represent:
Figure BSA00000355547400073
Embodiment 6
Present embodiment provides the compound of a kind of formula (VIII) expression:
Embodiment 7
Present embodiment provides the compound of a kind of formula (VIII) expression:
Embodiment 8～11
Have the structure that formula I is represented according to embodiment 8～11, and the substituting group on it is listed in the table 1.
Table 1
Embodiment 8 Embodiment 9 Embodiment 10 Embodiment 11
R 01～R 03 H D H H
R 04～R 07 H H D H
R 8～R 11 H H H H
R 12～R 15 H H H H
R 16～R 25 H H H D
Rx COC 2H 5 COC 2H 5 CH 2OCOC 2H 4NH 2 CH 2OP(OH) 3
R Y COC 2H 4NH 2 CON(C 2H 5)CH 2COOH CH 2OP(OH) 3 COC 2H 5
The foregoing description only is explanation technical conceive of the present invention and characteristics, and its purpose is to let the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences of doing based on spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.

Claims (6)

1. formula I compound and pharmacologically acceptable salt thereof,
Figure FSA00000355547300011
It is characterized in that: in the said formula I:
R 01, R 02, R 03, R 04, R 05, R 06, R 07, R 08, R 09, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R 20, R 21, R 22, R 23, R 24, R 25Be hydrogen or deuterium independently;
R XAnd R YIndependently for being selected from a kind of in the following groups:
H；
COC nH 2n+1；
COC nH 2nNH 2；
COC nH 2nNHC nH 2n+1；
COC nH 2nN(C nH 2n+1)C mH 2m+1；
COC nH 2nN(COC nH 2n+1)C mH 2m+1；
CON(C nH 2n+1)C nH 2nCOOH；
CH 2OCOC nH 2nNH 2；
CH 2OCOC nH 2nNHC nH 2n+1；
CH 2OCOC nH 2nN(C nH 2n+1)C mH 2m+1；
CH 2OCOC nH 2nN(COC nH 2n+1)C mH 2m+1；
CH(CH 3)OCOC nH 2nNH 2，
CH(CH 3)OCOC nH 2nNHC nH 2n+1；
CH(CH 3)OCOC nH 2nNHCOC nH 2n+1；
CH 2OP(OH) 3；
CH(CH 3)OP(OH) 3；
CONC nH 2n+1CH(R AA)COOH；
CH 2OCOCH(R AA)NHC nH 2n+1；
CH 2OCOCH(R AA)NHCOC nH 2n+1；
CH(CH 3)OCOCH(R AA)NHC nH 2n+1；
COCH(R AA)NHC nH 2n+1；
COCH(R AA)NHCOC nH 2n+1；
COCH(R AA)N(C nH 2n+1)C mH 2m+1；
COCH(R AA)N(COC nH 2n+1)C mH 2m+1；
And
Figure FSA00000355547300022
In the above-mentioned chemical formula, R AAThe amino acid side chain of expression dietary protein origin and/or non-dietary protein origin;
R MExpression OH, OC nH 2n+1, OCOC nH 2n+1, NH 2, NH (C nH 2n+1), N (C nH 2n+1) 2, SH, SC nH 2n+1, SCOC nH 2n+1, CN, F, Cl, Br or I;
N, m are the integer between 1～6 independently,
R XAnd R YBe not H simultaneously.
2. compound according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: n is 2 or 3.
3. compound according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: a kind of in the compound that is selected from formula II～(VIII) expression of said compound.
Figure FSA00000355547300023
4. described compound of each claim and pharmacologically acceptable salt thereof are used for the application that prevents and/or treats osteoporosis, improve the medicine of female dimacteric syndrome relative disease as selective estrogen receptor modulators in the claim 1 to 3.
5. described compound of each claim and pharmacologically acceptable salt thereof the purposes in the preparation indication medicine relevant in the claim 1 to 3 with oestrogenic hormon.
6. purposes according to claim 5; It is characterized in that: the said indication relevant with estrogen function comprises that bone loss, fracture, osteoporosis, cartilage sex change, endometriosis, uterus fiber disease, hot flush, LDL cholesterol levels increase, cardiovascular disorder, recognizing ability infringement, brain degenerative disease, restenosis, gynaecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, mammary cancer and osteoporosis after mammary cancer, uterus carcinoma, prostate cancer, the menopause.
CN2010105545711A 2010-11-23 2010-11-23 Benzothiophene compound and application thereof in preventive and/or treatment medicine for breast cancer and osteoporosis Pending CN102477033A (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015000867A1 (en) * 2013-07-03 2015-01-08 Glaxosmithkline Intellectual Property Development Limited Benzothiophene derivatives as estrogen receptor inhibitors
CN105008343A (en) * 2013-02-19 2015-10-28 诺华股份有限公司 Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders
US9993514B2 (en) 2013-07-03 2018-06-12 Glaxosmithkline Intellectual Property Development Limited Compounds
US10604506B2 (en) 2017-01-26 2020-03-31 Arvinas Operations, Inc. Modulators of estrogen receptor proteolysis and associated methods of use
US10647698B2 (en) 2016-12-01 2020-05-12 Arvinas Operations, Inc. Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders
US10865202B2 (en) 2016-09-15 2020-12-15 Arvinas Operations, Inc. Indole derivatives as estrogen receptor degraders
US11220515B2 (en) 2018-01-26 2022-01-11 Yale University Imide-based modulators of proteolysis and associated methods of use
US11883393B2 (en) 2019-12-19 2024-01-30 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of androgen receptor

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105008343A (en) * 2013-02-19 2015-10-28 诺华股份有限公司 Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders
CN105008343B (en) * 2013-02-19 2017-12-08 诺华股份有限公司 Alternatively benzothiophene derivative of property ERs degradation agent and combinations thereof
CN105452244A (en) * 2013-07-03 2016-03-30 葛兰素史克知识产权开发有限公司 Benzothiophene derivatives as estrogen receptor inhibitors
JP2016523875A (en) * 2013-07-03 2016-08-12 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Benzothiophene derivatives as estrogen receptor inhibitors
US9988376B2 (en) 2013-07-03 2018-06-05 Glaxosmithkline Intellectual Property Development Limited Benzothiophene derivatives as estrogen receptor inhibitors
US9993514B2 (en) 2013-07-03 2018-06-12 Glaxosmithkline Intellectual Property Development Limited Compounds
WO2015000867A1 (en) * 2013-07-03 2015-01-08 Glaxosmithkline Intellectual Property Development Limited Benzothiophene derivatives as estrogen receptor inhibitors
US10865202B2 (en) 2016-09-15 2020-12-15 Arvinas Operations, Inc. Indole derivatives as estrogen receptor degraders
US11584743B2 (en) 2016-09-15 2023-02-21 Arvinas Operations, Inc. Indole derivatives as estrogen receptor degraders
US10647698B2 (en) 2016-12-01 2020-05-12 Arvinas Operations, Inc. Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders
US10899742B1 (en) 2016-12-01 2021-01-26 Arvinas Operations, Inc. Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders
US11104666B2 (en) 2016-12-01 2021-08-31 Arvinas Operations, Inc. Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders
US11597720B2 (en) 2016-12-01 2023-03-07 Arvinas Operations, Inc. Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders
US11384063B2 (en) 2017-01-26 2022-07-12 Arvinas Operations, Inc. Modulators of estrogen receptor proteolysis and associated methods of use
US10604506B2 (en) 2017-01-26 2020-03-31 Arvinas Operations, Inc. Modulators of estrogen receptor proteolysis and associated methods of use
US11220515B2 (en) 2018-01-26 2022-01-11 Yale University Imide-based modulators of proteolysis and associated methods of use
US11834460B2 (en) 2018-01-26 2023-12-05 Yale University Imide-based modulators of proteolysis and associated methods of use
US11883393B2 (en) 2019-12-19 2024-01-30 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of androgen receptor

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