CN107382853A - 3- arylquinolines, its preparation method and medical usage - Google Patents
3- arylquinolines, its preparation method and medical usage Download PDFInfo
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- CN107382853A CN107382853A CN201710798278.1A CN201710798278A CN107382853A CN 107382853 A CN107382853 A CN 107382853A CN 201710798278 A CN201710798278 A CN 201710798278A CN 107382853 A CN107382853 A CN 107382853A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
Abstract
The present invention relates to medicinal chemistry art, and in particular to formula I 3 arylquinolines.Such compound can alternatively property estrogenic agents, treating or preventing a variety of medical indications related to post-menopause syndrome, be particularly suitable for treatment ER (+) type breast cancer.Meanwhile such compound can also be used for preparing the purposes as angiogenesis inhibitors medicine.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of 3- arylquinolines.Such compound can be made
For SERM, a variety of medical indications related to post-menopause syndrome are treated or prevented, particularly
Suitable for treating ER- (+) type breast cancer.Meanwhile such compound can also be used for preparing as angiogenesis inhibitors medicine
Purposes.
Background technology
Tumour is the disease characterized by abnormal cell hyperplasia out of control and diffusion.ACS 2014《The whole world
The cancer fact and data》Report display：The whole world in 2012 increases 14,000,000 cases of cancers newly and has 8,200,000 people death altogether, wherein
Newly-increased 3,070,000 cancer patients of China simultaneously cause about 2,200,000 people dead, account for the 21.9% and 26.8% of global total amount respectively.Report
Predict that swift and violent growing trend will be presented in global cases of cancer, by 14,000,000 people of 2012, cumulative year after year to 2025 1900
Ten thousand people, 24,000,000 people were up to by 2035.Cancer has become the major disease for seriously endangering human health and life, so far
Still without very satisfied treatment method.Therefore, outside necessary operative treatment, drug therapy approach increasingly becomes prevention
With a kind of important means for suppressing breast cancer, it is extremely urgent to develop the efficient antineoplastic of low toxicity.
Research finds that breast cancer has exception is close to contact with estrogen and estrogen receptor path.In normal condition
Under, development of the estrogen to reproductive system plays vital effect with maintenance, such as promotes mammary epithelium cell and intrauterine
Growth, the differentiation of theca cell；Bone, cardiovascular system, nervous system are also had a certain impact：Such as keep bone density and reduction
The risk that osteoporosis occurs, protects cardiovascular system, and can adjust cognitive function and row by reducing cholesterol levels
For.A series of this physiological action realizes that ERs (ER) is that estrogen receptor leads to by estrogen receptor path
Lu Zhongyi important albumen, belong to transcription factor nuclear receptor superfamily member, and one kind can be combined with DNA response original papers
The ligand dependent transcription factor, important adjustment effect is played in the life processes such as reproduction, development and metabolism.
A kind of multiple tumor of estrogen-dependent of ER- (+) type breast cancer, seriously endanger women's health.Correlative study
Breast cancer cell growth can be promoted by disclosing estrogen and being combined with ER.Classical ER mediation signal transduction pathway is as follows：Estrogen exists
After being combined in endochylema with ER, ER is promoted to be dissociated from heat shock protein, the compound that then estrogen is formed with its acceptor
[Estradiol (E2)-ER] conformation change and make acceptor occur homodimer, this homologous dimerization nanocrystal composition with
Estrogen response element (ERE) combines on target gene, and raises the related co-activation factor, starts the transcription of target gene, promotes breast
The growth of adenocarcinoma cell.
Selective estrogen conditioning agent (SERMs) is that one kind can be combined with ER, in different target tissues according to cell category
With the difference of hormonal milieu, the compound of ER activators or antagonist can be shown as.The SERMs medicines listed at present include
Tamoxifen, Raloxifene, Lasofoxifene, Bazedoxifene etc. more than ten is planted, and wherein Tamoxifen is the first generation
SERMs representative medicine, since approval listing in 1977, the head of prevention and auxiliary treatment women ER- (+) type breast cancer is turned into
Medicine is selected, studies have found that：Long-term use of Tamoxifen easily induces carcinoma of endometrium and drug resistance, it also occur that venous blood
The side effects such as bolt, vasodilation；Second generation SERMs using Raloxifene as representative, compared to Tamoxifen, it induces intrauterine
The probability of film cancer is low, but its clinical therapeutic efficacy is not so good as Tamoxifen, has been mainly used in menopause since approval listing in 2007
The prevention and treatment of women with breast cancer and osteoporosis afterwards.To sum up, study new effect significantly, the SERMs of Small side effects be
Chemoprophylaxis and a focus for the treatment of breast cancer.
Breast cancer is not only a kind of hormone-dependent neoplasm, or blood vessel dependent tumors, growth in breast cancer, invades
During the entire process of attacking, be in progress and shifting, the angiogenesis of tumour is important step therein.Body vessel is generated by endogenous
Angiogenic factors and anti-angiogenesis regulated and controled, balance between the two controls " switch " of angiogenesis.
Under former (predominantly anoxic, the inflammation and metabolic stress) effect of suitable stimulation, many angiogenic factors and anti-blood
Pipe generation factor balance is broken, and angiogenic factors are in clear superiority, and tumour initially forms new vessels.Up to now,
The factor relevant with Tumor Angiongesis has kind more than 30, its vascular endothelial growth factor (vascular
Endothelial growth factor, VEGF) be the most strong vasoactive endothelial cell being currently known growth because
Son.Different phase precedence table of the different angiogenesis factors often during tumor development reaches, and VEGF is as rush tumour
The key factor of angiogenesis, the whole expression during tumor development.
Therefore we combine the architectural feature of common SERMs and VEGFR inhibitor, have synthesized a kind of 3- aryl quinolines
Class compound, to play a part of SERMs, while there is certain inhibitory action to angiogenesis.
The content of the invention
The invention discloses formula I 3- arylquinolines.Prove that such compound can be for through pharmacological evaluation
ER- (+) type breast cancer has certain therapeutic action.Meanwhile available for the purposes prepared as angiogenesis inhibitors medicine.
Compounds of formula I structure of the present invention is as follows：
Wherein R1、R2、R3H, OH, halogen, CF are represented independently of one another3Straight or branched C1-C8Alkoxy or benzyloxy.
R represents unsubstituted or Y substituted straight chains or side chain C1-C6Alkyl；
Wherein Y is represented
Wherein R4、R5The C of H, straight or branched is represented independently of one another1-C6Alkyl, phenyl；Or R4、R5Coupled
N forms 5-7 members saturation or unsaturated heterocycle together, and the heterocycle is further containing the 1-3 hetero atoms for being selected from O, N, S；And institute
Heterocycle is stated by 1-3 selected from halogen, OH, NO2, straight or branched C1-C4Alkyl, CF3Substituent substitution；
The halogen is F, Cl, Br, I.
Preferably,
R1、R2、R3H, OH, C are represented independently of one another1-C4Alkoxy；
R represents unsubstituted or Y substituted straight chains or side chain C1-C3Alkyl；
Wherein Y is represented
Wherein R4、R5The C of H, straight or branched is represented independently of one another1-C4Alkyl；Or R4、R5Coupled N is together
5-6 member saturated heterocyclics are formed, the heterocycle is further selected from O, N, S hetero atom containing 1-3；And the heterocycle is by 1-3 C1-
C4Alkyl substitutes.
It is furthermore preferred that
R1、R2、R3H, OH, OCH are represented independently of one another3；
R represents the mono-substituted methyl of Y；Wherein Y represents N (CH3)2、N(CH2CH3)2、N(CH2)4、N(CH2)5、N(CH2CH2)2O、N(CH2CH2)2NCH3。
The structure and numbering of the compounds of this invention are as follows：
Formula I
The code name of compound is equal to the compound structure corresponding to above code name in pharmacological evaluation and embodiment.
The pharmaceutically acceptable salt and prodrug that the compound of Formula I of the present invention is formed are also included in the present invention.
The invention further relates to compounds of formula I and the Pharmaceutical composition of pharmaceutically acceptable carrier composition.
Here is partial pharmacologic experiment and the result of the compounds of this invention：
Mtt assay test MCF-7 Cells Proliferation of Human Breast Cancer experiments
Method of testing：MCF-7 breast cancer cells are with the RPMI1640 nutrient solution cultures containing 10% hyclone, life of taking the logarithm
Long-term cell is used to test, and adjustment cell density is 2 × 104Individual/mL, 96 orifice plates are inoculated in, after cultivating 12 hours, add 100 μ
The pastille culture medium in l/ holes, sample ultimate density are 2 × 10-4mol/L、1×10-4mol/L、1×10-5mol/L、1×10- 6Mol/L and 1 × 10-7Mol/L, each 3 multiple holes of concentration, testing drug is replaced as a control group with the culture medium of same volume,
20 μ l/ hole MTT (concentration 5mg/ml) are added after continuing culture 48 hours, after cultivating 4h, supernatant is abandoned, adds the μ of DMSO 150
L/ holes, determined with enzyme mark detector at 492nm wavelength per hole absorbance (A) value, cell proliferation inhibition rate is calculated by formula：Suppression
Rate processed=(control group A value-experimental group A values)/(control group A value-blank group A values) × 100%, and calculate IC50。
Mtt assay tests HUVEC cellular antiproliferative activity experiments
Human umbilical vein endothelial cells (human umbilical vein endothelial cell, HUVEC) are VEGF/
VEGFR action target, often it is used to test the anti-angiogenesis activity of VEGFR-2 inhibitor.The same MCF- of mtt assay method of testing
7 cells.
ER α receptor affinities are tested
Method of testing：The every kind of accurate weighing of testing compound, DMSO solvents is added into mother liquor, then using ES2
It is 100 μM that Screening Buffer, which prepare testing compound solution to concentration,.2X is prepared using ES2Screening Buffer
Fluorescent ligands make final Fluorescent ligands concentration be 9nM with ER α mixed liquors, and ER α concentration is 30nM.It is first in 384 hole black microwell plates
50 μ l compounds are added per hole, then 50ul 2X Fluorescent ligands and ER α mixed solutions are added per hole.Add 50ul estradiol simultaneously
Solution (100 μM), 50ul 2X Fluorescent ligands compare as 100% competition binding with ER α mixed solutions, add 50ul
Buffer, 50ul 2X Fluorescent ligands compare and added 100ul Buffer works as 0% competition binding with ER α mixed solutions
For blank control.Lucifuge operates.(20-25 DEG C) incubation 2h of room temperature, measures fluorescence polarization value mP.ER α relative binding affinities=
(blank group mP- experimental group mP)/(blank group mP- estradiol group mP) × 100%.
The part the pharmacological results of the compounds of this invention：
Using Tamoxifen and Raloxifene as positive control, MCF-7 cells have been carried out to the pyrimidines of synthesis
Proliferation experiment, result of study show that most compounds go out preferable inhibitory activity to MCF-7 cells shows.While with
Sunitinib is positive control, carries out HUVEC cell proliferation experiments to the pyrimidines of synthesis, experimental result is shown greatly
Part of compounds has good inhibiting effect to the propagation of HUVEC cells, shows such synthesized compound for blood vessel
The propagation of endothelial cell.Using Tamoxifen as in the ER α receptor affinities affinity experiment of control, majority of compounds exists
Under 50 μM of concentration, there is preferable affinity for ER α acceptors.Therefore such compound can be adjusted alternatively property ERs
Agent is saved, for treating or preventing a variety of medical indications related to post-menopause syndrome, is particularly suitable for treating ER- (+)
Type breast cancer.Meanwhile such compound can also be used for preparing and be used as angiogenesis inhibitors medicine.
The present invention provides the preparation method of formula I quinolines.The preparation method is route 1.
Route 1：
Reaction condition：A) EDCI, HOB T, Et3N, DCM, room temperature, 10h；B) DMF, POCl3, 0 DEG C -100 DEG C, 4h,；c)
Cs2CO3, Pd (OAc)2, BINAP, dioxane, backflow, 16h；d)ClCOCH2Cl, Et3N, DCM, 0 DEG C, 0.5h,；E) DMF,
K2CO3, KI, room temperature, 5h；f)BBr3, DCM, 0 DEG C, 12h.
Embodiment (embodiment is used only to the explanation present invention, rather than for limiting the present invention)
The preparation of part of compounds is implemented as follows：
1H-NMR nuclear magnetic resonance is by Bruker AV300 types (300MHz) nmr determination (TMS is internal standard compound), matter
Spectrum is respectively by Shimadzu GC/MS-QP2010 types mass spectrograph (EI-MS), Agilent1100LC-MSD-Trap/SL type mass spectrographs
(ESI-MS) determine.
Column chromatography is 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel (Haiyang Chemical Plant, Qingdao) with silica gel, is eluted
Agent is petroleum ether-ethyl acetate system or chloroform-methanol system.Thin-layer chromatography (TLC) GF254 thin layer chromatography boards (Yan Taijiang
Friendly silica gel development corporation, Ltd.)；TLC expansion system is petroleum ether-ethyl acetate system or chloroform-methanol system, is added if necessary
Enter a small amount of acetic acid；TLC irradiates display under ZF7 types ultraviolet analysis instrument for three purposed (Henan Gongyi Yu Hua Instrument Ltd.).Part
Compound purity is detected using Shimadzu HPLC under 254nm, and mobile phase is methanol/water system.
Embodiment 1
The preparation of N- (3- methoxyphenyls) -2- (4- methoxyphenyls) acetamides (3)
By homoanisic acid 2 (5g, 30.1mmol), EDCI (5.78g, 30.1mmol), HOBt (4.06g,
30.1mmol) it is dissolved in 100mL CH2Cl2In, stirred 1 hour at 0 DEG C.Then by 3- aminoanisoles (1) (3.7g,
30.1mmol) it is added in mixture and is stirred at room temperature 10 hours.Reaction solution is washed with saturated nacl aqueous solution.Decompression is steamed
Organic layer is sent out, obtains white solid 3 (7.8g, 96%).MS (ESI, m/z)：272.1[M+H]+
Embodiment 2
The preparation of 2- chloro- 7- methoxyl groups -3- (4- methoxyphenyls) quinoline (4)
DMF (3mL, 38.7mmol) is added drop-wise to POCl under ice bath3In (12mL, 129mmol) and stir 30 minutes.It will change
Compound 3 (7g, 25.8mmol) is added to stirring in mixture and, to dissolved clarification, is heated to 100 DEG C and reacts 4 hours.Then by mixture
Pour into frozen water, be extracted with ethyl acetate.Organic layer is evaporated under reduced pressure.Column chromatography purifies, and obtains yellow solid 4 (5g, 65%).MS
(ESI, m/z)：301[M+H]+
Embodiment 3
N1The preparation of-(7- methoxyl groups -3- (4- methoxyphenyls) quinoline -2- bases) benzene-Isosorbide-5-Nitrae-diamines (5)
By compound 4 (5g, 16.7mmol), p-phenylenediamine (2.7g, 25mmol), Pd (OAc)2(0.19g,
0.83mmol), BINAP (1g, 1.67mmol) and Cs2CO3(8.1g, 25mmol) is added in 50mL dioxane, is protected in nitrogen
Under be heated to reflux 10 hours.After filtering, be evaporated under reduced pressure reaction solution, column chromatography be purified to compound as yellow oil 5 (3.8g,
62%).1H-NMR (300MHz, DMSO-d6)δ：6.54-7.73 (m, 13H, Ar-H, NH), 4.80 (brs, 2H, NH2), 3.86
(s, 3H, OCH3), 3.83 (s, 3H, OCH3).MS (ESI, m/z)：372.1[M+H]+
Embodiment 4
The chloro- N- of 2- (4- ((7- methoxyl groups -3- (4- methoxyphenyls) quinoline -2- bases) amino) phenyl) acetamide (6)
Prepare
Under ice bath, chloracetyl chloride (0.7mL, 8.9mmol) is added drop-wise to compound 5 (3g, 8.1mmol) and triethylamine
(1.68mL, 12.1mmol) is in 20mL CH2Cl2Mixed solution in.Reaction uses saturated nacl aqueous solution washing reaction after 1 hour
Liquid, solvent is evaporated under reduced pressure, obtains yellow solid 6 (3.5g, 97%).MS (ESI, m/z)：448.1[M+H]+
Embodiment 5
2- (dimethylamino)-N- (4- ((7- methoxyl groups -3- (4- methoxyphenyls) quinoline -2- bases) amino) phenyl) second
The preparation of acid amides (I-1a)
By compound 6 (0.4g, 0.89mmol), K2CO3(0.24g, 1.78mmol) and with dimethylamine hydrochloride (72mg,
0.89mmol) add in 5mL DMF, stir 8h at room temperature.Reaction solution is poured into water, precipitation is collected by filtration, column chromatography purifies,
Obtain yellow solid I-1a (0.35g, 86%).mp：65-67℃；1H-NMR (300MHz, CDCl3)δ：9.06 (s, 1H, NHCO),
6.78-7.79 (m, 13H, Ar-H, NH), 3.96 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.08 (s, 2H, COCH2), 2.39
(s, 6H, N (CH3)2)；13C-NMR(CDCl3)δ：167.94,160.42,159.15,151.46,147.91,136.26,
136.01,131.74,130.07,128.82,127.69,122.80,119.51,119.41,118.52,114.86,114.35,
105.62,63.17,54.97,54.90,45.54；HRMS(ESI)m/z calcd for C27H28N4O3[M+H]+457.2234。
Embodiment 6
(lignocaine)-N- (4- ((7- methoxyl groups -3- (4- methoxyphenyls) quinoline -2- bases) amino) phenyl) acetamide
(I-2a) preparation
Yellow solid I-2a (0.31g, 72%) is obtained using with compound I-1a identical methods.mp：61-63℃；1H-
NMR (300MHz, CDCl3)δ：9.36 (s, 1H, NHCO), 6.77-7.76 (m, 13H, Ar-H, NH), 3.96 (s, 3H, OCH3),
3.91 (s, 3H, OCH3), 3.16 (s, 2H, COCH2), 2.63 (q, J=6.9,4H, N (CH2 CH3)2), 1.09 (t, J=7.1,6H,
N(CH2 CH3 )2)；13C-NMR(CDCl3)δ：169.30,160.42,159.16,151.48,147.92,136.19,136.01,
131.78,130.08,128.86,127.67,122.79,119.50,119.38,118.52,114.88,114.35,105.62,
57.64,54.97,54.91,48.39,11.98；HRMS(ESI)m/z calcd for C29H32N4O3[M+H]+485.2547
Embodiment 7
2- (pyrrolidinyl)-N- (4- ((7- methoxyl groups -3- (4- methoxyphenyls) quinoline -2- bases) amino) phenyl) acetyl
The preparation of amine (I-3a)
Yellow solid I-3a (0.3g, 70%) is obtained using with compound I-1a identical methods.mp：81-83℃；1H-NMR
(300MHz, CDCl3)δ：9.07 (s, 1H, NHCO), 6.78-7.79 (m, 13H, Ar-H, NH), 3.96 (s, 3H, OCH3), 3.91
(s, 3H, OCH3), 3.29 (s, 2H, COCH2), 2.71 (brs, 4H, N (CH2 CH2)2), 1.87 (brs, 4H, N (CH2 CH2 )2)；13C-NMR(CDCl3)δ：168.37,160.42,159.15,151.47,147.91,136.24,136.03,131.77,
130.08,128.83,127.70,122.80,119.63,119.43,118.52,114.88,114.35,105.60,59.25,
54.98,54.92,54.12,23.59；HRMS(ESI)m/z calcd for C29H30N4O3[M+H]+483.2391, found
483.2398。
Embodiment 8
2- (piperidyl)-N- (4- ((7- methoxyl groups -3- (4- methoxyphenyls) quinoline -2- bases) amino) phenyl) acetamide
(I-4a) preparation
Yellow solid I-4a (0.32g, 72%) is obtained using with compound I-1a identical methods.mp：174-176℃；1H-
NMR (300MHz, CDCl3)δ：9.23 (s, 1H, NHCO), 6.78-7.79 (m, 13H, Ar-H, NH), 3.96 (s, 3H, OCH3),
3.91 (s, 3H, OCH3), 3.08 (s, 2H, COCH2), 2.56 (brs, 4H, N (CH2 CH2)2CH2), 1.63 (brs, 4H, N
(CH2 CH2 )2CH2), 1.50 (brs, 2H, N (CH2CH2)2 CH2 )；13C-NMR(CDCl3)δ：168.16,160.42,159.15,
151.46,147.91,136.22,136.03,131.79,130.08,128.83,127.70,122.79,119.46,118.52,
114.89,114.35,105.60,62.29,54.98,54.92,54.44,25.84,23.17；HRMS(ESI)m/z calcd
for C30H32N4O3[M+H]+497.2547。
Embodiment 9
2- (morpholinyl)-N- (4- ((7- methoxyl groups -3- (4- methoxyphenyls) quinoline -2- bases) amino) phenyl) acetamide
(I-5a) preparation
Yellow solid I-5a (0.32g, 70%) is obtained using with compound I-1a identical methods.mp：93-95℃；1H-
NMR (300MHz, CDCl3)δ：9.01 (s, 1H, NHCO), 6.79-7.78 (m, 13H, Ar-H, NH), 3.96 (s, 3H, OCH3),
3.90 (s, 3H, OCH3), 3.79 (t, 4H, N (CH2 CH2 )2O), 3.15 (s, 2H, COCH2), 2.64 (t, 4H, N (CH2 CH2)2O)
；13C-NMR(CDCl3)δ：167.09,160.45,159.17,151.42,147.88,136.48,136.07,131.42,
130.07,128.79,127.72,122.80,119.56,119.43,118.55,114.93,114.36,105.60,66.57,
61.95,54.97,54.91,54.78,53.31；HRMS(ESI)m/z calcd for C29H30N4O4[M+H]+499.234。
Embodiment 10
2- (pyrrolidinyl)-N- (4- ((7- methoxyl groups -3- (4- methoxyphenyls) quinoline -2- bases) amino) phenyl) acetyl
The preparation of amine (I-6a)
Yellow solid I-6a (0.29g, 64%) is obtained using with compound I-1a identical methods.mp：81-84℃；1H-
NMR (300MHz, CDCl3)δ：9.11 (s, 1H, NHCO), 6.78-7.79 (m, 13H, Ar-H, NH), 3.96 (s, 3H, OCH3),
3.90 (s, 3H, OCH3), 3.15 (s, 2H, COCH2), 2.68 (brs, 4H, N (CH2 CH2)2NCH3), 2.53 (brs, 4H, N
(CH2 CH2 )2NCH3), 2.34 (s, 3H, N (CH2CH2)2NCH3 )；13C-NMR(CDCl3)δ：167.48,160.43,159.16,
151.44,147.89,136.35,136.05,131.59,130.08,128.81,127.70,122.80,119.48,119.45,
118.54,114.91,114.36,105.60,61.35,54.97,54.91,54.78,52.92,45.50；HRMS(ESI)m/z
calcd for C30H33N5O3[M+H]+512.2656。
Embodiment 11
2- (dimethylamino)-N- (4- ((7- hydroxyls -3- (4- hydroxy phenyls) quinoline -2- bases) amino) phenyl) acetamide
(I-1b) preparation
Compound I-1a (0.4mmol) is dissolved in the anhydrous CH of 10mL2Cl21mol/L BBr is added under middle ice bath under ice bath3/
CH2Cl2Solution (3.2mL, 3.2mmol), after reacting 12h, it is poured into water, adds NaHCO3Adjust pH to 8.Ethyl acetate extracts,
Organic phase is dry with being decompressed to, and column chromatography obtains yellow solid I-1b (81mg, 45%).mp：213-215℃；1H-NMR (300MHz,
DMSO-d6)δ：9.76 (brs, 2H, OH), 9.58 (s, 1H, NHCO), 6.83-7.83 (m, 13H, Ar-H, NH), 3.05 (s, 2H,
COCH2), 2.28 (s, 6H, N (CH3)2)；13C-NMR(DMSO-d6)δ：168.07,158.57,157.25,151.78,147.58,
136.60,136.33,132.62,130.24,128.50,127.51,122.95,121.99,119.86,119.69,118.10,
116.00,114.70,113.83,108.36,63.25,45.34；HRMS(ESI)m/z calcd for C25H24N4O3[M+H]+
429.1921。
Embodiment 12
2- (lignocaine)-N- (4- ((7- hydroxyls -3- (4- hydroxy phenyls) quinoline -2- bases) amino) phenyl) acetamide
(I-2b) preparation
Yellow solid I-2b (84mg, 46%) is obtained using with prepare compound I-2a identical methods.mp：143-146℃
；1H-NMR (300MHz, DMSO-d6)δ：9.72-9.85 (m, 2H, OH), 9.53 (s, 1H, NHCO), 6.84-7.83 (m, 13H,
Ar-H, NH), 3.14 (s, 2H, COCH2), 2.56 (q, 4H, N (CH2 CH3)2), 1.00 (t, 6H, N (CH2 CH3 )2)；13C-NMR
(DMSO-d6)δ：169.16,158.58,157.25,151.79,147.60,136.69,136.37,132.33,130.26,
128.53,127.54,122.96,119.96,119.51,118.12,114.88,114.71,108.38,57.35,47.92,
11.92；HRMS(ESI)m/z calcd for C27H28N4O3[M+H]+457.2234。
Embodiment 13
2- (pyrrolidinyl)-N- (4- ((7- hydroxyls -3- (4- hydroxy phenyls) quinoline -2- bases) amino) phenyl) acetamide
(I-3b) preparation
Yellow solid I-3b (96mg, 53%) is obtained using with prepare compound I-2a identical methods.mp：147-150℃
；1H-NMR (300MHz, DMSO-d6)δ：9.73 (brs, 2H, OH), 9.56 (s, 1H, NHCO), 6.82-7.73 (m, 13H, Ar-H,
NH), 3.22 (s, 2H, COCH2), 2.59 (brs, 4H, N (CH2 CH2)2), 1.75 (brs, 4H, N (CH2 CH2 )2)；13C-NMR
(DMSO-d6)δ：168.23,158.55,157.22,151.78,147.58,136.58,136.33,132.61,130.24,
128.50,127.52,122.94,119.86,119.70,118.09,115.98,114.67,108.34,59.46,53.70,
23.44；HRMS(ESI)m/z calcd for C27H26N4O3[M+H]+455.2078。
Embodiment 14
2- (piperidyl)-N- (4- ((7- hydroxyls -3- (4- hydroxy phenyls) quinoline -2- bases) amino) phenyl) acetamide (I-
Preparation 4b)
Yellow solid I-4b (95mg, 51%) is obtained using with prepare compound I-1a identical methods.mp：151-153℃
；1H-NMR (300MHz, DMSO-d6)δ：9.67-9.82 (m, 2H, OH), 9.53 (s, 1H, NHCO), 6.82-7.73 (m, 13H,
Ar-H, NH), 3.04 (s, 2H, COCH2), 2.46 (brs, 4H, N (CH2 CH2)2CH2), 1.57 (brs, 4H, N (CH2 CH2 )2CH2),
1.26 (brs, 2H, N (CH2CH2)2 CH2 )；13C-NMR(DMSO-d6)δ：167.98,158.56,157.22,151.79,
147.57,136.65,136.35,132.47,130.25,128.52,127.53,122.95,119.93,119.60,118.10,
115.98,114.69,108.34,62.57,54.08,25.43,23.50；HRMS(ESI)m/z calcd for C28H28N4O3
[M+H]+469.2234。
Embodiment 15
2- (morpholinyl)-N- (4- ((7- hydroxyls -3- (4- hydroxy phenyls) quinoline -2- bases) amino) phenyl) acetamide (I-
Preparation 5b)
Yellow solid I-5b (91mg, 47%) mp is obtained using with prepare compound I-1b identical methods：160-161℃；1H-NMR (300MHz, DMSO-d6)δ：9.79 (s, 1H, OH), 9.65 (s, 1H, NHCO), 9.59 (s, 1H, OH), 6.82-7.73
(m, 13H, Ar-H, NH), 3.65 (brs, 4H, N (CH2 CH2 ) O), 3.11 (s, 2H, COCH2), 2.50 (brs, 4H, N (CH2 CH2)
O)；13C-NMR(DMSO-d6)δ：167.40,158.55,157.22,151.78,147.57,136.69,136.36,132.48,
130.24,128.52,127.52,122.96,119.88,119.77,118.10,115.99,114.70,108.33,66.05,
61.98 53.18；HRMS(ESI)m/z calcd for C27H26N4O4[M+H]+471.2027。
Embodiment 16
2- (methyl piperazine base)-N- (4- ((7- hydroxyls -3- (4- hydroxy phenyls) quinoline -2- bases) amino) phenyl) acetamide
(I-6b) preparation
Yellow solid I-6b (83mg, 43%) is obtained using with prepare compound I-1b identical methods.mp：164-167℃
；1H-NMR (300MHz, DMSO-d6)δ：9.73 (brs, 2H, OH), 9.55 (s, 1H, NHCO), 6.85-7.91 (m, 13H, Ar-H,
NH), 3.09 (s, 2H, COCH2), 2.51 (brs, 4H, N (CH2 CH2)2NCH3), 2.40 (brs, 4H, N (CH2 CH2 )2NCH3),
2.18 (s, 3H, N (CH2CH2)2NCH3 )；13C-NMR(DMSO-d6)δ：167.67,158.55,157.21,151.78,147.56,
136.65,136.36,132.47,130.24,128.51,127.52,122.94,119.91,119.61,118.08,115.96,
114.68,108.30,61.72,54.50,52.66,45.66；HRMS(ESI)m/z calcd for C28H29N5O3[M+H]+
484.2343。
Claims (6)
1. general formula I, its pharmaceutically acceptable salt or its prodrug：
Wherein R1、R2、R3H, OH, halogen, CF are represented independently of one another3Straight or branched C1-C8Alkoxy or benzyloxy；
R represents unsubstituted or Y substituted straight chains or side chain C1-C6Alkyl；
Wherein Y is represented
Wherein R4、R5The C of H, straight or branched is represented independently of one another1-C6Alkyl, phenyl；Or R4、R5Coupled N mono-
Rise and form 5-7 members saturation or unsaturated heterocycle, the heterocycle is further containing the 1-3 hetero atoms for being selected from O, N, S；It is and described miscellaneous
Ring is by 1-3 selected from halogen, OH, NO2, straight or branched C1-C4Alkyl, CF3Substituent substitution；
The halogen is F, Cl, Br, I.
2. compound according to claim 1, its pharmaceutically acceptable salt or its prodrug, wherein R1、R2、R3Each solely
On the spot represent H, OH, C1-C4Alkoxy；
R represents unsubstituted or Y substituted straight chains or side chain C1-C3Alkyl；
Wherein Y is represented
Wherein R4、R5The C of H, straight or branched is represented independently of one another1-C4Alkyl；Or R4、R5Coupled N is formed together
5-6 member saturated heterocyclics, the heterocycle are further selected from O, N, S hetero atom containing 1-3；And the heterocycle is by 1-3 C1-C4Alkane
Base substitutes.
3. compound according to claim 1, its pharmaceutically acceptable salt or its prodrug, wherein R1、R2、R3Each solely
On the spot represent H, OH, OCH3；
R represents the mono-substituted methyl of Y；Wherein Y represents N (CH3)2、N(CH2CH3)2、N(CH2)4、N(CH2)5、N(CH2CH2)2O、N
(CH2CH2)2NCH3。
A kind of 4. pharmaceutical composition, wherein the compound containing any one of claims 1 to 3, its pharmaceutically acceptable salt
Or its prodrug and pharmaceutically acceptable carrier.
5. the compound of any one of claims 1 to 3, its pharmaceutically acceptable salt or its prodrug alternatively property estrogen
Receptor modulators are treated or prevented in a variety of medical indications related to post-menopause syndrome, and treatment ER- (+) breast cancer
Purposes.
6. the compound of any one of claims 1 to 3, its pharmaceutically acceptable salt or its prodrug are as Agiogenesis inhibition
Purposes of the agent in tumour is treated.
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