CN102477010A - Indole derivative and application thereof to preparing medicine for preventing and/or treating breast cancer osteoporosis - Google Patents

Indole derivative and application thereof to preparing medicine for preventing and/or treating breast cancer osteoporosis Download PDF

Info

Publication number
CN102477010A
CN102477010A CN2010105545675A CN201010554567A CN102477010A CN 102477010 A CN102477010 A CN 102477010A CN 2010105545675 A CN2010105545675 A CN 2010105545675A CN 201010554567 A CN201010554567 A CN 201010554567A CN 102477010 A CN102477010 A CN 102477010A
Authority
CN
China
Prior art keywords
formula
coc
ococ
nhc
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN2010105545675A
Other languages
Chinese (zh)
Inventor
殷建明
朱惠霖
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SUZHOU BORUI PARMACEUTICALS Inc
Original Assignee
SUZHOU BORUI PARMACEUTICALS Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SUZHOU BORUI PARMACEUTICALS Inc filed Critical SUZHOU BORUI PARMACEUTICALS Inc
Priority to CN2010105545675A priority Critical patent/CN102477010A/en
Publication of CN102477010A publication Critical patent/CN102477010A/en
Pending legal-status Critical Current

Links

Abstract

The invention relates to a novel indole derivative and application thereof to preparing a medicine for preventing and/or treating breast cancer osteoporosis. The indole derivative disclosed by the invention is an ideal selective estrogen receptor modulator and can be used for treating or preventing various indications relative to estrogen, in particular breast cancer osteoporosis after menopause. The indole derivative has lower oxidative metabolism and higher effective bioavailability, therefore having the advantages of less application dosage, better tolerance and little side effect.

Description

Indole derivatives and prevent and/or treat the purposes in the mammary cancer osteoporosis agents in preparation
Technical field
The present invention relates to indole derivatives and 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 thunder Lip river former times branch 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, provides a kind of selective estrogen receptor modulators that can be used as to be used for the indole derivatives that prevents and/or treats osteoporosis, improve the medicine of female dimacteric syndrome relative disease.
For solving above technical problem, the present invention takes following technical scheme:
Compound and pharmacologically acceptable salt thereof with logical formula I:
Figure BSA00000355546400031
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 25, R 26, R 27, R 28, R 29, R 30, R 31, R 32Be 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 BSA00000355546400041
And
Figure BSA00000355546400042
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.
According to the present invention, n is preferably 2 or 3.
According to the present invention, the compound of representational compound such as formula II, formula III, formula IV, formula (V), formula VI, formula (VII) and formula (VIII) expression.
Figure BSA00000355546400043
Figure BSA00000355546400051
Figure BSA00000355546400061
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.
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:
Indole derivatives first pass effect provided by the 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 BSA00000355546400071
Embodiment 2
The compound that present embodiment provides a kind of formula III to represent:
Figure BSA00000355546400072
Embodiment 3
The compound that present embodiment provides a kind of formula IV to represent:
Figure BSA00000355546400081
Embodiment 4
Present embodiment provides the compound of a kind of formula (V) expression:
Figure BSA00000355546400082
Embodiment 5
The compound that present embodiment provides a kind of formula VI to represent:
Figure BSA00000355546400091
Embodiment 6
Present embodiment provides the compound of a kind of formula (VII) expression:
Figure BSA00000355546400092
Embodiment 7
Present embodiment provides the compound of a kind of formula (VIII) expression:
Figure BSA00000355546400093
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 D
R 04～R 06 H H D H
R 07～R 10 H H H H
R 11～R 12 H H H H
R 13～R 16 H H H H
R 17～R 20 H H D H
R 21～R 32 H D 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 that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.

Claims (6)

1. the compound and the pharmacologically acceptable salt thereof that have logical formula I:
Figure FSA00000355546300011
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 25, R 26, R 27, R 28, R 29, R 30, R 31, R 32Be 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 FSA00000355546300022
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: said n is 2 or 3.
3. compound according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: said compound is a kind of in the compound of formula II, formula III, formula IV, formula (V), formula VI, formula (VII) and formula (VIII) expression.
Figure FSA00000355546300031
Figure FSA00000355546300041
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.
CN2010105545675A 2010-11-23 2010-11-23 Indole derivative and application thereof to preparing medicine for preventing and/or treating breast cancer osteoporosis Pending CN102477010A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2010105545675A CN102477010A (en) 2010-11-23 2010-11-23 Indole derivative and application thereof to preparing medicine for preventing and/or treating breast cancer osteoporosis

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2010105545675A CN102477010A (en) 2010-11-23 2010-11-23 Indole derivative and application thereof to preparing medicine for preventing and/or treating breast cancer osteoporosis

Publications (1)

Publication Number Publication Date
CN102477010A true CN102477010A (en) 2012-05-30

Family

ID=46089801

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2010105545675A Pending CN102477010A (en) 2010-11-23 2010-11-23 Indole derivative and application thereof to preparing medicine for preventing and/or treating breast cancer osteoporosis

Country Status (1)

Country Link
CN (1) CN102477010A (en)

Similar Documents

Publication Publication Date Title
CN102477033A (en) Benzothiophene compound and application thereof in preventive and/or treatment medicine for breast cancer and osteoporosis
CN102083426B (en) Cannabinoids in combination with non -cannabinoid chemotherapeutic agents (e.g. serm or alkylating agents)
Jing et al. Preventive and ameliorating effects of citrus D-limonene on dyslipidemia and hyperglycemia in mice with high-fat diet-induced obesity
US5912273A (en) Triphenylethylenes compositions
Ke et al. Scutellarin suppresses migration and invasion of human hepatocellular carcinoma by inhibiting the STAT3/Girdin/Akt activity
CN103702975B (en) ENCLO metabolite and uses thereof
EP2037905A2 (en) Treatment of vasomotor symptoms with selective estrogen receptor modulators
MXPA04012998A (en) Tricyclic steroid hormone nuclear receptor modulators.
AR035564A1 (en) SELECTIVE MODULATORS OF STROGEN RECEIVERS IN COMBINATION WITH STROGENS
Martarelli et al. Hypericum perforatum methanolic extract inhibits growth of human prostatic carcinoma cell line orthotopically implanted in nude mice
CN103570694B (en) Preparation of icaritin and derivatives thereof and application of icaritin and derivatives of icaritin in tumor treatment
CZ212297A3 (en) Use of 3,4-diphenylchromans for preparing a medicament intended for treating or prophylaxis of gynecological diseases
TW586928B (en) Pharmaceutical compositions for treating or preventing benign prostatic hyperplasia
ZA200500217B (en) 9-Alpha-substituted estratienes as selectively active estrogen
CN102477017A (en) Tetrahydronaphthalene derivative and application thereof to preparing medicine for preventing and/or treating breast cancer osteoporosis
Robben et al. Effects of intestinal microbial bile salt sulfatase activity on bile salt kinetics in gnotobiotic rats
JPWO2008139952A1 (en) Microtubule disrupting agent and cancer cell growth inhibitor containing the same
CN102477010A (en) Indole derivative and application thereof to preparing medicine for preventing and/or treating breast cancer osteoporosis
JPWO2004035089A1 (en) Treatment for hormone-dependent cancer
WO2002015901A1 (en) Myricetin as an inhibitor of serotonin n-acetyltransferase
CN107007611A (en) Application of the nomegestrol acetate in the medicine for preparing treatment carcinoma of endometrium
KR20040041619A (en) Use of extracts of the genus Cimicifuga as organoselective medicines for treating diseases of the genitourinary system caused by sex hormones
CN102040585A (en) Selective estrogen receptor regulator
EA201000097A1 (en) 8-BETA-SUBSTITUTED ESTRATRIENES AS A SELECTIVE ACTIVE STROGEN
CN110433160A (en) A kind of compound that treating liver fibrosis and its application

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20120530

WD01 Invention patent application deemed withdrawn after publication