CN106478763A - New estrogenic associated receptor alpha inhibitor and its medical usage - Google Patents
New estrogenic associated receptor alpha inhibitor and its medical usage Download PDFInfo
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Abstract
The invention discloses a kind of new estrogenic associated receptor α (ERR α) inhibitor, it is compound of formula I and its pharmaceutically acceptable salt or solvate, and the pharmaceutical composition containing this compound can be used for preparing the medicine of the diseases such as prevention and treatment breast carcinoma, cervical cancer, ovarian cancer, carcinoma of prostate, gastric cancer, colon cancer.
Description
Technical field
The present invention relates to a kind of new estrogenic associated receptor alpha inhibitor and its medical usage.
Background technology
Estrogen all plays an important role in the growth of organism, growth, metabolic process, and its horizontal abnormality also may be used
Can be some tumorigenic inducements.Estrogen by with target cell in Specific nuclear receptors-estrogen receptor (Estrogen
Receptor, ER) α and β combine adjusting its physiological effect.Studies have found that, a class need not can produce life with ligand binding
Orphan nuclear receptor-the estrogen-related receptor (Estrogen-related receptor, ERR) of thing function has also assisted in female
The sophisticated signal transduction system of hormone, and closely related with the disease that estrogen causes.
ERR and ER belongs to the 3rd nuclear receptor together, mainly includes 3 kinds of hypotypes：ERRα(NR3B1)、ERRβ(NR3B2)、ERRγ
(NR3B3).Wherein, ERR α is to be screened with the cDNA of the DNA binding domain (DBD) of ER α for probe first by Giguere etc..
ERR α encoding gene is located at human chromosome 11q13 site, and total length about 20kb, including 7 exons and 6 introns, exon 2
Encode the conservative DBD of its height with 3.(pertinent literature：Giguere V, et al.Nature, 1988,331 (6151)：91-94)
ERR α mainly comprises 3 functional domains：N-terminal domain (N terminal domain, NTD), DBD, C-terminal part knot
Close domain (Ligand binding domain, LBD).Contain in NTD mobilizing function area 1 (Activation function 1,
AF1), contain AF2 in LBD.The relatively low NTD of conservative degree is primarily involved in the covalent modification after transcribing, such as phosphorylation and little ubiquitin
Relevant modifications.2 zinc fingerses are contained, for identifying and combining the special sequence of regulatory region in target gene DNA in the DBD of ERR α
Row.Comprise 1 ligand binding pocket positioned at the high conservative LBD of C-terminal, for Receptor dimerization；And A mainly lead to AF2 cross and some
Secondary navigable span is [as peroxisome proliferator receptor y secondary navigable span 1 α (Peroxisome proliferator-
Activated receptor γ coactivator 1 α and 1 β, PGC-1 α and PGC-1 β)] or auxiliary repressor [as receptor is mutual
Action protein 140 (Receptor interacting protein 140, RIP140)] etc. generating function interact, come
Adjust the transcriptional activity of nuclear receptor.Sequence analysis find, ERR α all has higher homology with classical ER in DBD and LBD region：
ERR α and the homology in DBD region for the ER α reach 68%, and the homology in LBD region has reached 33%, such architectural feature
The signal transduction participating in estrogen for ERR α provides architecture basics.(pertinent literature：Giguere V. Trends
Endocrinol Metab, 2002,13 (5)：220-225；Stein RA, et al.Endocr Relat cancer, 2006,
13(Suppl 1)：S25-S32)
ERR α expression in the tissue is wider, and all has expression from embryonic development period to adult stage.Heart, intestinal, brain,
ERR α all can be detected in spinal cord, brown fat, skeleton, kidney and endometrial carcinoma cell；ERR α is in the heart, kidney, intestinal, brown fat
Expression in need to organizing Deng energy height is higher, and the expression in the organs such as liver, lung, vagina is relatively low.ERR α is becoming
Almost omnipresent in body tissue, this means that it take part in many physiological process, is particularly participated in the physiology of regulation and control by ER α
Process, and affect the signal path of ER α.
ER α and ERR α all can with dimeric forms and estrogen response element (Estrogen response element,
ERE) combine to play its biological effect, and ERR α can also be with monomeric form and estrogen-related receptor response element
(Estrogen-related receptor response element, ERRE) combines.Studies have found that, ERR α can by with
ER α forms heterodimer person and ER α competition binding ERE, plays effect during some gene pairss estrogen responses.This
Outward, ER α dimer also can identification function ERRE, the signal path of therefore ER α and ERR α is almost completely overlapped.(pertinent literature：
Johnston SD, et al.Mol Endocrinol, 1997,11 (3)：342-352).
Early stage is concentrated mainly on the physiological process such as carbohydrate metabolism, lipid metabolism, ERR α and some metabolics to the research of ERR α
The generation of disease is related, such as obesity, diabetes, osteoporosises etc..The metabolic process that ERR α participates in body mainly has sugared generation
Thank, lipid metabolism, mitochondrial oxidative metabolism and adaptive energy metabolism.In carbohydrate metabolism, ERR α is mainly by glyconeogenesis metabolism
Approach enters tricarboxylic acid cycle (Tricarboxylic acid cycle, TCA) with derivatization pyruvate sugared in mitochondrion
Regulation and control, thus play its regulating and controlling effect in carbohydrate metabolism.In lipid metabolism, many regulation and control mitochondrial fatty acid beta-oxidation paths
Gene (as middle chain acyl-CoA dehydrogenase, malonyl coenzyme A decarboxylase) be all ERR α target gene.In mitochondrial oxidation
In metabolic process, ERR α, by acting on to control the promoter of target gene with secondary navigable span PGC-1 α, makes regulation and control oxidative phosphorylation
Gene expression raise, thus regulating and controlling mitochondrial oxidative metabolism.It is subject to the severe change of external environment in body (as cold, hungry
Starve) when, the rise of ERR α can make body make energy production and the feedback utilizing, and reaches optimal adaptive state.
Increasing research shows in recent years, the estrogen such as breast carcinoma that ERR α and estrogen cause, carcinoma of endometrium
Dependent tumors are closely related.Additionally, the generation of numerous non-estrogen-dependent tumor such as adenocarcinoma of stomach, colorectal cancer etc. also with
The expression of ERR α is related.ERR α high expression in the cancers such as breast carcinoma, ovarian cancer, carcinoma of endometrium, carcinoma of prostate, colon cancer,
It is the biological label of prognosis malas.Reason is probably, on the one hand, ERR α can be joined with competitive binding estrogen response element ERE
With the signal transduction of estrogen, the tumor such as this negative breast carcinoma with ER, carcinoma of endometrium is closely related；On the other hand, ERR α
Maintain the high-energy metabolism state of cancerous cell, growth and metastasis of tumours is promoted by Wa Shi effect (Warburg effect), be situated between
Lead cancer angiogenesis, adjust tumor microenvironment.(pertinent literature：Kraus RJ, et al.J Biol Chem, 2002,277
(27)：24826-24834；Fujimoto J, et al.J Steroid Biochem Mol Biol, 2009,116 (1-2)：
71-75；Cavallini A, et al.Eur J Cancer, 2005,41 (10)：1487-1494)
There are some researches show, ERR alpha inhibitor XCT790 (1a, table 1) can effectively reduce the low of the carcinoma of prostate of the high expression of ERR α
Oxygen tolerates situation；When introducing siRNA targeting ERR α, can effectively suppress propagation, glucose uptake and the Fructus Vitis viniferae of colon cancer cell
The lipogenesis of sugar mediation.Therefore, ERR α is probably the novel targets of a potential therapy-related tumor, little point of exploitation ERR α
Sub- inhibitor has potential using value in terms of the personalized treatment of cancer.(Zou C, et al.J Pathol, 2014,
233：61-73；Bernatchez G, et al.Carcinogenesis, 2013,34：2253-2261)
The ERR α micromolecular inhibitor of report has at present：XCT-790 (1a), thiazolidine -2,4- cyclohexadione compounds 1b,
(structural formula are as follows) such as Benzazole compounds 1c, flavone compound kaempferol 1d, triazole compound 1e and steroid 1f.
Due to due to efficacy and saferry, in above-mentioned inhibitor, not yet there is approved listing antitumor drug.Therefore, develop and more pacify
Effectively new E RR alpha inhibitor has urgent clinical demand entirely.
Content of the invention
The technical problem to be solved in the invention is to provide a kind of new estrogenic associated receptor α (ERR α) inhibitor.Solution
Certainly the technical scheme of above-mentioned technical problem is as follows：
The present invention provides a kind of new E RR alpha inhibitor, and it is compound of formula I or its pharmaceutically acceptable salt or solvent
Compound：
The present invention another object is that offer compound of formula I or its pharmaceutically acceptable salt or solvate in treatment tumor
Application in disease.
Preferably, described tumor disease is any one in following disease：(1) breast carcinoma；(2) cervical cancer；(3) intrauterine
Film cancer；(4) ovarian cancer；(5) carcinoma of prostate；(6) gastric cancer；(7) colon cancer.
The present invention also provides a kind of prevention or the pharmaceutical composition treating above-mentioned tumor disease, contains in described pharmaceutical composition
There are the compound of formula I of therapeutically effective amount or its pharmaceutically acceptable salt or solvate as active component and pharmaceutically can connect
The carrier being subject to.
The present invention adopts technique scheme, and compared with prior art, compound of formula I is likely to become therapy-related tumor disease
The novel drugs molecule of disease, has broad application prospects.
Present invention also offers the preparation method of compound of formula I.Concrete synthetic route is as follows：
The preparation of starting material compound 1 is with reference to Chinese patent application 201210420988.8.The concrete conjunction of compound of formula I
Become step referring to embodiment 2.
Brief description
Fig. 1 is that the compound of formula I of the present invention suppresses Binding experiment (time-resolved fluorescence resonance energy to molecular level ERR α
Transfer techniques, TR-FRET) result.
Specific embodiment
Illustrate present disclosure below by embodiment.In the present invention, embodiments discussed below be in order to
Preferably illustrate the present invention, be not for limiting the scope of the present invention.
Embodiment 1
Detection technique (the Time-Resolved Fluoresence of use time resolved fluorescent resonance energy transfer
Resonance Energy Transfer Assay, TR-FRET Assay) on a molecular scale test the present invention compound
Competition binding activity to ERR α.
This example illustrates compound according to the present invention can suppress ERR α and coactivator PGC-1 effectively
The combination of α, illustrates compound competitive binding ERR α (molecular level) involved in the present invention.TR-FRET is this area work
Technology familiar to personnel.
FRET (Fluoresence Resonance Energy Transfer) i.e. FRET (fluorescence resonance energy transfer), is to be based on
The energy transfer of Liang Ge fluorescence group (donor and receptor).In the case that Liang Ge fluorescence group is close, phase between biomacromolecule
Interaction can be with measuring with fluorescence labels and energy transfer between the two.When two group close enough, swash
Rise (as flash lamp or laser) excite fluorogenic donor, energy transfer can be caused to receptor, thus receptor sends spy
The fluorescence of standing wave length.
TR-FRET, compared with FRET, is usually used in the screening of medicine, and we use LanthaScreenTMEstrogen
Related Receptor alpha TR-FRET Coactivator Assay is used for analyzing LBD area and the assisted activation of ERR α
The interaction of factor PGC-1 α, after the LBD area of ERR α is combined with its inverse agonist XCT-790, conformation becomes
Change, weaken with the adhesion of coactivator PGC-1 α, in the signal weakening of 520nm, therefore can be used to screening and ERR α
The compound of competition binding.
Concrete operations are as follows：
Plus 30 μ l the TR-FRET auxiliary adjustment factor buffer G of 1M DTT to 5.97ml in, be made into and completely buffer liquid G；
Plus DMSO completely buffers in liquid G to above-mentioned, the solution being made into DMSO final concentration of 2% as negative control, 384
10 this solution of μ l are added in orifice plate；
With the compound of formula I in DMSO by a certain percentage the stepwise dilution present invention and XCT-790, it is diluted to 12 concentration ladders
Degree；
With completely buffering liquid G, above-mentioned gradient dilution liquid is diluted 50 times again；
After mixing, the compound solution in previous step is shifted in 10 μ l to 384 orifice plates；
Prepare 4 × ERR α-LBD (20nM) buffer with the liquid G that completely buffers of pre-cooling；
5 μ l above-mentioned 4 × ERR α-LBD buffer is taken to add in 384 orifice plates；
4 × fluorescein-labeled PGC-1 α (2 μM) and 4 × Tb-GST antibody is prepared with completely buffering liquid G under room temperature
(20nM) mixed solution；
The above-mentioned fluorescent antibody mixed liquor preparing of 5 μ l is taken to add 384 orifice plates；
After jiggling mixing, by 384 orifice plate lucifuge incubated at room 1h；
Detect the wavelength at 520nm and 495nm by instrument PerkinElmer Envision, with emissive porwer ratio
(520/495) calculate the competition binding activity to ERR α for the compound；
Test result indicate that, compound of formula I according to the present invention can dose-dependently antagonism ERR α and PGC-1 α
In conjunction with showing that compound of formula I can significantly suppress ERR α (IC50=3.46 μM), result is shown in accompanying drawing 1.
Embodiment 2
The preparation of compound of formula I
Step 1, the preparation of compound 2
3 beta-hydroxy oleanane -13 (18)-alkene -28- carboxylic acid (1) (20g, 0.044mol) is dissolved in THF (600mL), point
Criticize and add LiAlH4(7g, 0.183mol).Stirred at reflux condition 1.5 hours.Add methanol and water quenching to go out, extracted with ethyl acetate
Take, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.White solid 2 is obtained through silica gel column chromatography after being spin-dried for
(17g, yield 88%).IR (film, cm-1) 3374,2928,2868,2359,1633,1455,1384,1359,1044,996,
971；1H NMR (300MHz, DMSO-d6) δ 3.60 (brs, 2H), 3.23 (dd, J=5.5,10.9Hz, 1H), 2.75-2.69
(m, 1H), 2.32 (d, J=14.1Hz, 1H), 1.93-0.72 (m, 22H), 1.18 (s, 3H), 0.99 (s, 3H), 0.94 (s,
3H), 0.86 (s, 6H), 0.77 (s, 3H), 0.74 (s, 3H)；13C NMR (75MHz, DMSO-d6) δ 136.9,130.9,77.3,
61.1,55.4,50.5,44.5,40.9,39.2,39.0,38.9,37.3,35.2,34.9,33.2,32.5,32.2,29.0,
28.7,27.6,26.1,25.1,24.8,22.0,21.8,18.6,18.0,16.6,16.4；ESI MS m/z 465.2[M+Na
]+；HRMS calcd for C30H50O2Na[M+Na]+M/z 465.37030, found 465.37059.
Step 2, the preparation of compound 3
Compound 2 (2g, 4.5mmol) is dissolved in pyridine (8mL), adds acetic anhydride (1.3mL, 13.5mmol).Room temperature is stirred
Mix overnight.Solvent evaporated, is subsequently adding water (100mL), is extracted with ethyl acetate (3 × 20mL), merges organic layer, saturated common salt
Water washing, anhydrous sodium sulfate drying.White solid 3 (2.1g, yield 88%) is obtained through silica gel column chromatography after being spin-dried for.IR (film,
cm-1) 3449,2926,2871,1740,1653,1456,1384,1242,1027,1005,985；1H NMR (300MHz,
CDCl3) δ 4.50 (dd, J=3.6,6.3Hz, 1H), 4.19 (d, J=6.8Hz, 1H), 4.00 (d, J=6.8Hz, 1H), 2.70
(dd, J=1.7,8.9Hz, 1H), 2.32 (d, J=8.5Hz, 1H), 2.05 (s, 3H), 2.04 (s, 3H), 1.91-1.85 (m,
1H), 1.78-0.90 (m, 21H), 1.17 (s, 3H), 0.93 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H), 0.86 (s, 3H),
0.84 (s, 3H), 0.74 (s, 3H)；13C NMR (75MHz, CDCl3) δ 171.2,170.8,138.7,128.9,80.8,64.8,
55.4,50.5,44.5,40.9,38.9,38.5,38.0,37.7,37.2,35.0,34.6,33.0,32.0,33.1,30.0,
28.0,26.1,25.2,24.4,23.6,21.6,21.5,21.2,21.0,18.2,17.7,16.6,16.4；ESI MS m/z
549.39[M+Na]+；HRMS calcd for C34H54O4Na[M+Na]+M/z 549.3920, found 549.3942.
Step 3, the preparation of compound 4
Compound 3 (0.5g, 0.95mol) is dissolved in isopropanol (25mL), adds aluminum isopropylate. (0.23g, 1.14mmol).
Stirred at reflux condition terminates to reaction.Solvent evaporated, is subsequently adding water (100mL) as far as possible, be extracted with ethyl acetate (3 ×
10mL), organic layer, saturated common salt water washing, anhydrous sodium sulfate drying are merged.White solid 4 is obtained through silica gel column chromatography after being spin-dried for
(330mg, yield 72%).IR (film, cm-1) 3317,2981,1592,1416,1306,1275,1261,1212,1135,
1056,1033,1016,764,750,678；1H NMR (300MHz, CDCl3) δ 4.53-4.47 (m, 1H), 3.61 (d, J=
11.3Hz, 1H), 3.57 (d, J=11.3Hz, 1H), 2.74-2.68 (m, 1H), 2.31 (dd, J=1.6,14.0Hz, 1H),
(1.95-0.94 m, 22H), 2.04 (s, 3H), 1.17 (s, 3H), 0.93 (s, 3H), 0.88 (s, 3H), 0.86 (s, 6H), 0.83
(s, 3H), 0.72 (s, 3H)；13C NMR (75MHz, CDCl3) δ 171.0,138.7,129.6,80.9,64.3,55.4,50.5,
44.5,40.9,39.6,38.9,38.5,37.8,37.2,35.1,34.6,33.3,32.7,32.1,30.3,28.0,26.4,
25.2,24.4,23.6,21.63,21.55,21.3,18.3,17.6,16.6,16.4；ESI MS m/z 507.38[M+Na]+；
HRMS calcd for C32H52O3Na[M+Na]+M/z 507.3814, found 507.3838.
Step 4, the preparation of compound 5
Compound 4 (2g, 4.1mmol) is dissolved in dichloromethane (80mL), adds pyridinium chlorochromate (1.3g, 6.2mmol).
It is stirred at room temperature and terminate to reaction.Solvent evaporated, obtains white solid 5 (1.7g, yield 85%) through silica gel column chromatography.IR (film,
cm-1) 3461,2946,2874,1736,1716,1456,1386,1369,1246,1027,1008,976,853,408；1H NMR
(300MHz, CDCl3) δ 9.35 (s, 1H), 4.53-4.47 (m, 1H), 2.81-2.76 (m, 1H), 2.45 (d, J=14.2Hz,
1H), 2.02-1.09 (m, 22H), 2.05 (s, 3H), 1.17 (s, 3H), 0.91 (s, 3H), 0.90 (s, 3H), 0.87 (s, 6H),
0.84 (s, 3H), 0.74 (s, 3H)；13C NMR (75MHz, CDCl3) δ 205.9,171.0,140.2,126.2,80.9,55.4,
51.7,50.6,44.3,41.1,40.7,38.5,37.7,37.2,36.3,34.7,32.7,32.6,32.0,29.6,28.0,
26.8,25.1,24.0,23.6,21.6,21.27,21.21,18.2,17.6,16.6,16.4；ESI MS m/z 505.37[M+
Na]+；HRMS calcd for C32H50O3Na[M+Na]+M/z 505.3658, found 505.3682.
Step 5, the preparation of compound 6
Compound 5 (4g, 8.3mmol) is dissolved in acetic acid (40mL), be subsequently adding 1，2-ethandithiol (3.5mL,
41.7mmol) with boron trifluoride diethyl etherate (46.5%, 10mL).It is stirred at room temperature and terminate to reaction.Then add water and be quenched, use acetic acid second
Ester extracts, and merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.White solid 6 is obtained through silica gel column chromatography after being spin-dried for
(4.6g, yield 99%).IR (film, cm-1) 3420,2924,2857,1734,1641,1456,1376,1245,1098,
1026,984；1H NMR (300MHz, CDCl3) δ 5.36 (s, 1H), 4.53-4.48 (m, 1H), 3.27-3.03 (m, 4H), 2.77-
2.71 (m, 1H), 2.33 (d, J=14.1Hz, 1H), 2.20-2.09 (m, 2H), 1.95-1.90 (m, 2H), 1.81-0.88 (m,
18H), 2.04 (s, 3H), 1.17 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H), 0.90 (s, 3H), 0.86 (s, 3H), 0.84
(s, 3H), 0.74 (s, 3H)；13C NMR (75MHz, CDCl3) δ 171.0,138.9,130.9,81.0,61.5,55.5,50.6,
44.3,41.0,38.7,38.6,38.5,38.3,37.7,37.2,35.1,34.8,34.2,31.7,29.9,28.0,27.9,
26.0,25.7,23.7,21.7,21.6,21.3,18.5,18.3,16.6,16.5.
Step 6, the preparation of compound 7
Compound 6 (300mg, 0.54mmol) is dissolved in ethanol (60mL), adds Raney Ni (6g).Stirred at reflux condition
Terminate to reaction.Sucking filtration, solvent evaporated, silica gel column chromatography obtains white solid 7 (235mg, yield 94%).IR (film, cm-1)
2936,2850,1728,1457,1375,1246,1143,1027,1014,981；1H NMR (300MHz, CDCl3)δ4.53-
4.48 (m, 1H), 2.68-2.62 (m, 1H), 2.26 (dd, J=2.1,13.8Hz, 1H), 2.04 (s, 3H), 1.86-0.79 (m,
22H), 1.15 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H), 0.88 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.84
(s, 3H), 0.70 (s, 3H)；13C NMR (75MHz, CDCl3) δ 171.0,134.3,133.3,81.0,55.5,50.7,44.7,
41.0,39.4,38.7,38.5,37.8,37.2,36.6,35.4,34.8,34.6,33.3,32.3,28.0,26.5,25.0,
24.1,23.8,23.7,21.7,21.3,18.3,17.7,16.6,16.4；ESI MS m/z 491.39[M+Na]+；HRMS
calcd for C32H52O2Na[M+Na]+M/z491.3865, found 491.3878.
Step 7, the preparation of compound of formula I
Compound 7 (160mg, 0.34mmol) is dissolved in methanol (15mL), is subsequently adding potassium hydroxide (0.3g).Reflux condition
Stir under part and terminate to reaction.Then add water (30mL) reaction is quenched, be extracted with ethyl acetate, merge organic layer, saturated common salt
Water washing, anhydrous sodium sulfate drying.White solid I (136mg, yield 90%) is obtained through silica gel column chromatography after being spin-dried for.mp 210-
213℃；[Lit 43.mp 205℃]；[α]D- 41.3 (c 0.22, CHCl3)；[Lit 43.[α]D- 44.7 (c 1.2,
CHCl3)]；IR (film, cm-1) 3419,2940,2359,2331,1456,1383,1362,1092,1038,1008,972；1H
NMR (300MHz, CDCl3) δ 3.26 (dd, J=5.5,10.8Hz, 1H), 2.69-2.61 (m, 1H), 2.26 (dd, J=2.1,
13.9Hz, 1H), 1.88-0.72 (m, 22H), 1.16 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H), 0.93 (s, 3H), 0.86
(s, 6H), 0.77 (s, 3H), 0.70 (s, 3H)；13C NMR (75MHz, CDCl3) δ 134.4,133.2,79.1,55.4,50.8,
44.7,41.0,39.4,38.9,38.7,37.3,36.7,35.5,34.9,34.6,33.3,32.4,28.1,27.4,26.5,
25.1,24.1,23.8,21.8,21.4,18.5,17.7,16.4,15.5.
Embodiment 3
Tablet
By the compound of formula I (50g) being obtained in embodiment 2, hydroxypropyl methylcellulose E (150g), starch (200g), poly- dimension
Ketone K30 is appropriate and magnesium stearate (1g) mixes, and pelletizes, tabletting.
Claims (4)
1. a kind of new estrogenic associated receptor α (ERR α) inhibitor, it be compound of formula I or its pharmaceutically acceptable salt or
Solvate.
2. compound of formula I or its pharmaceutically acceptable salt or solvate purposes in treatment tumor disease.
3. purposes as claimed in claim 2, described tumor disease is any one in following disease：Breast carcinoma, cervical cancer, son
Endometrial carcinoma, ovarian cancer, carcinoma of prostate, gastric cancer or colon cancer.
4. a kind of prevention or the pharmaceutical composition treating tumor disease as claimed in claim 3, contain in described pharmaceutical composition
The compound of formula I of therapeutically effective amount or its pharmaceutically acceptable salt or solvate are as active component and pharmaceutically acceptable
Carrier.
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