CN113024460B - Tetrahydroisoquinoline compounds as estrogen receptor and histone deacetylase double-target compounds, and synthesis method and application thereof - Google Patents
Tetrahydroisoquinoline compounds as estrogen receptor and histone deacetylase double-target compounds, and synthesis method and application thereof Download PDFInfo
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- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
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Abstract
The invention discloses a tetrahydroisoquinoline compound serving as an estrogen receptor and histone deacetylase double-target compound, a synthesis method and application. The invention can simultaneously target Estrogen Receptor (ER) and Histone Deacetylase (HDAC), plays double roles of degrading ER and inhibiting HDAC, and can be used for preparing medicaments for treating human breast cancer.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a tetrahydroisoquinoline compound capable of targeted degradation of estrogen receptor alpha (ER alpha) and inhibition of Histone Deacetylase (HDAC), a synthesis method and application thereof.
Background
Estrogen Receptors (ER), which are one of 48 members of the Nuclear Receptor (NR) superfamily, exert a hormonal action by binding to Estrogen ligands, such as Estradiol (E2), often cause various diseases, such as endometrial cancer, ovarian cancer, osteoporosis, arteriosclerosis, alzheimer's disease, etc., especially breast cancer, with ER. Currently, hormone replacement therapy is mainly adopted for clinically treating breast cancer. For example, first-line drug Selective Estrogen Receptor Modulators (SERMs), tamoxifen (Tamoxifen), raloxifene (Raloxifene), and selective estrogen receptor down-regulators (SERDs), such as Fulvestrant (Fulvestrant), and the like. However, these drugs often have side effects, such as tamoxifen, which may cause drug resistance and increase the risk of endometrial cancer after long-term use.
Histone and non-histone acetylation levels play an important role, among others, in gene translation, cell cycle and structural function of microtubules. Histone Acetyltransferases (HATs) and Histone Deacetylases (HDACs) regulate the balance of cellular acetylation levels. It has been found that dysbalance between HATs and HDACs can lead to tumorigenesis. The HDACs family contains 18 kinds of deacetylases, and is different in structure, substrate specificity, enzyme activity mechanism, subcellular localization, and tissue specificity, and can be divided into 4 different families, i.e., I, II, III, and IV, according to their homology to yeast cell deacetylase sequences. Histone deacetylase 6 (HDAC 6) belongs to the IIb family, shuttles in the cytoplasm and nucleus, is mainly localized to the cytoplasm, and is the only isozyme in HDACs that has two functionally homologous catalytic domains and a C-terminal ubiquitin-binding zinc finger domain. Thus, HDAC6 can regulate a range of cellular processes by deacetylating or ubiquitinating substrate proteins, affecting human diseases. In recent years, it has been found that HDACs can regulate the level of acetylation at several sites on the estrogen signaling pathway, and can affect gene transcription in the ER. Therefore, HDACs are also considered as a new target for treating breast cancer, and histone deacetylase inhibitors (HDACi) can inhibit the activity of HDACs in breast cancer cells, so that the acetylation degree of histone in breast cancer cells is increased, thereby inhibiting the proliferation of breast cancer cells. Tamoxifen-resistant breast cancer cell line T47D cells expressed higher HDAC6 than non-resistant T47D cells, and treatment with Tubacin, a specific small molecule inhibitor of HDAC6, was effective in inhibiting the in vivo tumorigenic capacity of tamoxifen-resistant T47D cells. At present, some ER-HDACI double-target conjugates have been reported, which have good inhibitory effect on breast cancer cells and have the potential of overcoming drug resistance.
Disclosure of Invention
The invention aims to: the invention provides a tetrahydroisoquinoline compound serving as an estrogen receptor and histone deacetylase double-target compound, which can simultaneously target ER alpha and HDAC6 and play double roles of degrading ER alpha and inhibiting HDAC.
Another object of the present invention is to provide a process for the preparation of the above compound or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a pharmaceutical composition.
The last object of the invention is to provide the application of the compound or the pharmaceutically acceptable salt thereof in preparing medicines for treating or preventing hormone receptor positive breast cancer and triple negative breast cancer.
The technical scheme is as follows: the present invention provides a compound capable of targeted degradation of ER α and effective inhibition of HDAC, or a pharmaceutically acceptable salt thereof, having the general formula (I):
wherein:
x is H or F;
y is selected from the following structures:
in particular, the compound capable of targeted degradation of ER α and effective inhibition of HDAC is selected from the compounds of table 1:
TABLE 1
The second aspect of the present invention provides a method for synthesizing the above compound, the method comprising the steps of:
(1) Heating and refluxing compound IA with hydrobromic acid to demethylate compound IB, preferably 48% hydrobromic acid;
(2) Condensing the compound IB with a compound IC under the action of a condensing agent HATU to obtain a compound ID;
(3) Reducing the compound ID under the action of sodium borohydride and iodine elementary substance to obtain a compound IE;
(4) Cyclizing the compound IE and the compound IF under an alkaline condition to obtain a compound IG;
(5) The compound IG is subjected to ester hydrolysis by using lithium hydroxide or hydroxamation by using hydroxylamine hydrochloride to obtain the compound of the formula I, and the specific reaction formula is as follows:
IF is
R is
In a third aspect, the present invention provides the use of the above compound, an isomer or a pharmaceutically acceptable salt thereof for the preparation of an estrogen receptor down-regulator.
The fourth aspect of the present invention provides the use of the above compound, an isomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a histone deacetylase inhibitor.
The fifth aspect of the present invention provides a use of the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing hormone receptor positive breast cancer and triple negative breast cancer. The sixth aspect of the present invention provides a composition, which includes the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for a significant error in the formula.
Has the advantages that:
compared with the prior art, the compound has better SERD activity, also has histone deacetylase inhibitory activity, and has the potential of overcoming drug resistance.
Drawings
FIG. 1 is a graph showing the results of an experiment in which the compounds of the present invention have ER α degradation.
Detailed Description
The NMR data of the final products and intermediates in the examples are DMSO-d6 or CDCl 3 -d3 is a solvent and TMS is an internal standard, determined by Bruker's 300MHz or 400MHz nuclear magnetic resonance apparatus; high Resolution Mass Spectrometry (HRMS) was determined by an Agilent model Q-TOF 6520 mass spectrometer.
Reagents used in the synthesis, purification and isolation of the compounds are: (1) column chromatography silica gel: 200 or 300 mesh silica gel is purchased from Qingdao ocean chemical industry; (2) HSGF254 TLC thin layer chromatography plate: purchased from the tobacco desk chemical research institute; (3) The conventional solvents used in the column chromatography elution system, such as petroleum ether, dichloromethane, ethyl acetate, methanol and the like, and chemical reagents required by the reaction are all commercially available chemical pure products or analytically pure products except for special instructions.
Example 1: (E) Synthesis of (I-1) -3- (4- (2- (2-fluoro-2-methylpropyl) -6-hydroxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) phenyl) acrylic acid
Synthesis route:
step 1:
compound IA (3 g,19.7 mmol) was dissolved in 20ml48% hydrobromic acid and heated at reflux for 5h. After the reaction, the reaction solution was cooled to room temperature, distilled under reduced pressure, and the solvent was dried by rotary drying to obtain a reddish brown solid IA (2.7g, 99.2%). 1 H NMR(300MHz，Methanol-d 4 )δ7.23-7.13(m，1H)，6.79-6.69(m，3H)，3.17(t，J＝7.7Hz，2H)，2.91(t，J＝7.6Hz，2H).
Step 2:
compound IB (2.2g, 10mmol) was dissolved in 20ml of N, N-Dimethylformamide (DMF), and N, N-diisopropylethylamine (DIPEA, 5ml, 3mmol) and IC-1 (1.17g, 11mmol) were added with stirring, and after stirring at room temperature for 10min under nitrogen protection, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 2.85g, 15mmol) was added under ice bath, and after completion of the reaction at room temperature for 2h. After the reaction, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried, and the solvent was evaporated under reduced pressure, and purified by column chromatography to give the desired product ID-1 (1.1g, 48%) 1 H NMR(300MHz，DMSO-d6)δ9.28(s，1H)，8.08(q，J＝5.1Hz，1H)，7.12-6.99(m，1H)，6.58(dt，J＝4.0，2.5Hz，3H)，3.30-3.19(m，2H)，2.64(dd，J＝8.3，6.6Hz，2H)，1.45(s，3H)，1.38(s，3H).
And step 3:
sodium borohydride (1g, 3mmol) and ID-1 (2g, 10mmol) were dissolved in 25ml of anhydrous tetrahydrofuran, and a solution of iodine in anhydrous tetrahydrofuran (25 ml) was slowly added dropwise at room temperature under a nitrogen atmosphere. After the dropwise addition, the reaction is carried out for 6 hours under nitrogen reflux. Cooling to room temperature after the reaction is finished, pouring the reaction solution into water, extracting by ethyl acetate, washing by saturated saline water, drying, distilling under reduced pressure to spin-dry the solvent, and carrying out column chromatographyPurification yielded the desired product IE-1 (1.2g, 64%). 1 H NMR(400MHz，DMSO-d 6 )δ9.30(brs，1H)，7.08(td，J＝7.6，0.9Hz，1H)，6.67-6.55(m，3H)，2.89-2.78(m，4H)，2.69(dd，J＝9.1，6.3Hz，2H)，1.36(s，3H)，1.31(s，3H).
And 4, step 4:
activated molecular sieves were added to a reaction flask, IE-1 (0.1g, 0.47mmol) and IF-1 (0.19g, 0.95mmol) were dissolved in dry toluene (2 ml), and triethylamine (0.3ml, 2mmol) was added and the reaction was carried out at 90 ℃ for 2h under nitrogen. After the reaction is finished, the temperature is reduced to room temperature, the reaction liquid is poured into water, extracted by ethyl acetate, washed by saturated saline solution, dried, subjected to reduced pressure distillation and spin-drying of the solvent, and purified by column chromatography to obtain the target product IG-1 (30mg, 16.0%). 1 H NMR(300MHz，Chloroform-d)δ7.71(d，J＝16.0Hz，1H)，7.49(d，J＝8.0Hz，2H)，7.34(s，1H)，6.66(d，J＝2.4Hz，1H)，6.62-6.52(m，2H)，6.45(dd，J＝16.0，4.0Hz，1H)，4.60(s，1H)，4.31(q，J＝7.1Hz，2H)，3.53-3.40(m，1H)，3.12-2.99(m，1H)，2.82(d，J＝16.8Hz，1H)，2.68(s，1H)，2.62(d，J＝14.9Hz，1H)，2.50(t，J＝14.5Hz，1H)，1.30(t，J＝10.9Hz，6H)，0.97-0.85(m，3H).
And 5:
compound IG-l (30mg, 0.25mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 ml) and water (1 ml), and lithium hydroxide (10mg, 0.42mmol) was added. The reaction was carried out overnight at room temperature, after completion of the reaction, the solvent was distilled off under reduced pressure, and purification by column chromatography gave the objective product I-1 (15mg, 53.8%). 1 H NMR(300MHz，Methanol-d 4 )δ7.75-7.63(m，1H)，7.56(dd，J＝8.3，2.0Hz，2H)，7.34(dd，J＝8.1，1.6Hz，2H)，6.62-6.58(m，1H)，6.54-6.44(m，3H)，4.61(s，1H)，3.44(dd，J＝11.6，5.4Hz，1H)，3.03(ddd，J＝14.9，9.1，5.2Hz，1H)，2.80(dt，J＝15.8，4.6Hz，1H)，2.72-2.56(m，2H)，2.51(d，J＝14.4Hz，1H)，1.31-1.24(m，3H)，1.21(d，J＝11.7Hz，3H).
Examples 2 to 20
The synthetic route is as follows:
step 1:
compound IA (3g, 19.7mmol) was dissolved in 20ml48% hydrobromic acid and heated to reflux for 5h. After the reaction, the reaction solution was cooled to room temperature, distilled under reduced pressure, and the solvent was dried by rotary drying to obtain a reddish brown solid IA (2.7g, 99.2%). 1 H NMR(300MHz，Methanol-d 4 )δ7.23-7.13(m，1H)，6.79-6.69(m，3H)，3.17(t，J＝7.7Hz，2H)，2.91(t，J＝7.6Hz，2H).
Step 2:
compound IB (2.2g, 10mmol) was dissolved in 20ml of N, N-Dimethylformamide (DMF), and N, N-diisopropylethylamine (DIPEA, 5ml, 3mmol) and IC-1 (1.17g, 11mmol) were added with stirring, and after stirring at room temperature for 10min under nitrogen protection, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 2.85g, 15mmol) was added under ice bath, and after completion of the reaction at room temperature for 2h. After the reaction, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried, and the solvent was evaporated under reduced pressure, and purified by column chromatography to give the desired product ID-1 (1.1g, 48.0%) 1 HNMR(300MHz，DMSO-d6)δ9.28(s，1H)，8.08(q，J＝5.1Hz，1H)，7.12-6.99(m，1H)，6.58(dt，J＝4.0，2.5Hz，3H)，3.30-3.19(m，2H)，2.64(dd，J＝8.3，6.6Hz，2H)，1.45(s，3H)，1.38(s，3H).
And step 3:
sodium borohydride (1g, 3mmol) and ID-1 (2g, 10mmol) were dissolved in 25ml of anhydrous tetrahydrofuran, and a solution of iodine in anhydrous tetrahydrofuran (25 ml) was slowly added dropwise at room temperature under nitrogen protection. After the dropwise addition, nitrogen gas is refluxed and reacted for 6 hours. After the reaction is finished, the temperature is reduced to room temperature, the reaction liquid is poured into water, extracted by ethyl acetate, washed by saturated saline solution, dried, distilled under reduced pressure to dry the solvent, and purified by column chromatography to obtain the target product IE-1 (1.2g, 64.0%). 1 H NMR(400MHz，DMSO-d 6 )δ9.30(brs，1H)，7.08(td，J＝7.6，0.9Hz，1H)，6.67-6.55(m，3H)，2.89-2.78(m，4H)，2.69(dd，J＝9.1，6.3Hz，2H)，1.36(s，3H)，1.31(s，3H).
And 4, step 4:
activated molecular sieves were added to a reaction flask, IE-1 (0.1g, 0.47mmol) and IF-16 (0.11g, 0.47mmol) were dissolved in dry toluene (2 ml), followed by addition of triethylamine (0.3ml, 2mmol) and reaction at 90 ℃ for 2h under nitrogen. After the reaction is finished, the temperature is reduced to room temperature, the reaction liquid is poured into water, extracted by ethyl acetate, washed by saturated saline, dried, subjected to reduced pressure distillation to spin-dry the solvent, and purified by column chromatography to obtain the target product IG-16 (50mg, 24.6%). 1 H NMR(300MHz，Chloroform-d)δ7.75(d，J＝8.0Hz，2H)，7.38(d，J＝8.1Hz，2H)，6.82(t，J＝5.1Hz，1H)，6.66(d，J＝2.2Hz，1H)，6.52(d，J＝2.5Hz，1H)，4.59(s，1H)，4.27(d，J＝3.5Hz，2H)，4.25(s，2H)，3.43(dt，J＝11.2，4.9Hz，1H)，3.14-2.97(m，1H)，2.82(d，J＝14.6Hz，1H)，2.76-2.61(m，2H)，2.58-2.34(m，1H)，1.40-1.29(m，6H)，1.27(s，1H)，1.24(s，1H)，1.20(s，1H).
Step 5
Hydroxylamine hydrochloride (4.67g, 67mmo 1) was dissolved in methanol (24 m 1), and a methanol solution (12 ml) of potassium hydroxide (5.61g, 100mmol) was dropped under ice bath, followed by reaction at 0 ℃ for 30min. And after the reaction is finished, carrying out suction filtration on the reaction liquid, and collecting filtrate, namely the methanol solution of hydroxylamine. The compound IG-16 (50mg, 0.12mmol) was added to a freshly prepared hydroxylamine methanol solution and reacted at room temperature for 2h, after completion of the reaction, the solvent was rotary-dried by distillation under reduced pressure and purified by column chromatography to give the desired product I-16 (15mg, 53.8%). 1 H NMR(400MHz，Methanol-d4)δ7.80(dd，J＝23.9，7.9Hz，2H)，7.39(d，J＝7.8Hz，2H)，6.59(s，1H)，6.46(d，J＝1.4Hz，2H)，4.60(s，1H)，4.03(s，2H)，3.43(d，J＝17.0Hz，1H)，3.26-2.82(m，2H)，2.72(s，2H)，2.63-2.11(m，1H)，1.30(s，6H).
Using procedures similar to those described above, the following other compounds of the invention were prepared.
TABLE 2 exemplary derivatives of Compounds I-16
Example 21: activity assay
Table 3 is the source of reagents used in the following activity tests.
TABLE 3 sources of reagents
Table 4 is the instrument source used for the following activity tests.
TABLE 4 sources of instruments
Pharmacological (antiproliferative) test of Compounds
Since MCF-7 cell anti-proliferation assays can be used to initially evaluate compounds for inhibition of ER-positive breast cancer in vitro, some of the compounds synthesized herein were subjected to in vitro MCF-7 anti-proliferation assays.
1. Experimental method
Human breast cancer MCF-7 cells were taken for the biological activity assay in the logarithmic growth phase, the density of the digested cell mass was diluted to 5 × 104 cells/ml with complete medium and the cell suspension was inoculated into 96-well plates with a row gun. Each 96-well plate is provided with a group of blank negative controls and a group of blank positive controls, the negative controls are replaced by the same volume of complete culture medium without adding drugs or cell suspensions, the positive controls are replaced by the same volume of complete culture medium containing 0.1 percent of DMSO without adding drugs. In addition, in order to prevent solvent evaporation of cell suspension in the central test area of the 96-well plate due to long-term placement in a cell culture chamber, 200. Mu.l of PBS buffer solution was added to the peripheral 36 wells. After the cells are paved, the cells are placed into a cell incubator for incubation for 24 hours. Then, the 96-well plate was taken out, and 100. Mu.l of complete medium containing the sample was added to each well so that the final concentrations of the samples to be tested were 80. Mu.M, 40. Mu.M, 20. Mu.M, 10. Mu.M, and 1. Mu.M in this order, and 3 duplicate wells were set for each concentration. After culturing in an incubator for 48 hours, 20. Mu.l of 5mg/ml MTT solution was added to each well in the dark, and the mixture was incubated in the incubator for 4 hours. And (3) taking out the 96-well plate, carefully sucking out the culture medium, adding 150 mu l of DMSO solution into each well, placing the well into a shaking instrument, shaking for 10min to completely dissolve out the purple crystals at the bottom, and detecting the light absorption value (OD) of the crystals in an enzyme-linked immunosorbent assay (ELIAS) instrument, wherein the detection wavelength is set to 490nm. The inhibition rate of each concentration is calculated according to the following formula, a concentration-inhibition rate curve is drawn by GraphPad Prism 7.0, and finally the IC of the compound is given 50 Value (inhibition = OD test-OD negative/OD positive-OD negative).
2. Results of the experiment
Table 5 shows the results of pharmacological (antiproliferative) experiments on the compounds.
Table 5 shows the results of pharmacological (antiproliferative) experiments on the compounds
The human breast cancer MCF-7 cell line is from Kyoho Kayki Biotechnology GmbH, and an estrogen receptor modulator tamoxifen and a histone deacetylase inhibitor SAHA are used as a control group.
Research results show that the compound of the invention has better inhibitory activity on MCF-7 cells.
Anti-proliferation activity experiment of (II) triple-negative breast cancer cell line MDA-MB-231
1. Experimental methods
The procedure and dosing concentration settings were the same as MCF-7, and MDA-MB-231 cells were dosed 24h after plating and incubated 24h after dosing.
2. Results of the experiment
Table 6 shows the results of the anti-proliferative Activity test of triple negative breast cancer cell line MDA-MB-231
Table 6 shows the results of the anti-proliferative Activity test of triple negative breast cancer cell line MDA-MB-231
| Compound | IC 50 (μM) | Compound | IC 50 (μM) |
| I-1 | - | I-2 | - |
| I-3 | - | I-4 | - |
| I-5 | 1.01 | I-6 | 0.38 |
| I-7 | - | I-8 | - |
| I-9 | - | I-10 | ＞80μM |
| I-11 | - | I-12 | - |
| I-13 | - | I-14 | - |
| I-15 | - | I-16 | - |
| I-17 | - | I-18 | - |
| I-19 | - | I-20 | - |
| Tamoxifen | ＞80μM | SAHA | 15.44 |
Research results show that the compound of the invention has better inhibitory activity on MDA-MB-23. And the structure-effect trend is consistent with MCF-7.
(III) determination of in vitro HDAC6 inhibitory Activity by fluorescence assay
To demonstrate that the compounds of the present invention have inhibitory effect on HDAC6, the inhibitory activity of HDAC6 of the compounds of the present invention was measured by fluorescence assay using non-selective HDAC inhibitor SAHA as a positive control.
The results of the experiment (Table 7) show that the compounds of the present invention exhibit certain inhibitory activity against HDAC6 at both 1. Mu.M and 0.1. Mu.M.
(IV) detection of ER alpha level by Western Blot method
In order to prove that the compound of the invention has ER alpha degradation effect, the down-regulation effect of the compound I-5, I-6, I-2, I-20, I-10 on the level of ER alpha protein is respectively tested by using a Western Blot method and Fulvestrant as a positive control.
1. Experimental method
After MCF-7 cells are treated by the compound, the culture medium is removed, PBS is used for washing for 2-3 times, protease inhibitor and RIPA lysate are sequentially added, the culture plate is repeatedly shaken to enable the cells to be in full contact with the culture plate, and then the cells are scraped by a scraper. Transferring the obtained cell suspension into a centrifuge tube, cracking on ice for 30min, repeatedly blowing with a pipette to promote cell lysis, and centrifuging (4 deg.C, 12,000g,10 min) to obtain supernatant as total protein solution. Protein concentration was determined using BCA protein quantitative assay kit according to kit instructions, then 5 x protein loading buffer was added at ratio of protein solution to protein loading buffer = 4: 1 and boiled in boiling water bath for 15min in preparation for next protein separation. An equal amount of the above protein solution was added to the gel loading well and prepared for electrophoresis, wherein the voltage of the concentrated gel was 75V and the voltage of the separation gel was 120V. And (5) electrophoretic until bromophenol blue just runs out, and then carrying out mold conversion. Stripping off the band of the target protein, sticking a PVDF membrane, transferring the band to the PVDF membrane through electrophoresis, and then sealing the band for 1h on a decoloring shaking table by using 5% skimmed milk. Primary antibody was added and incubated overnight at 4 ℃ followed by three washes with TBST for 5min each. Secondary antibody was added and incubated at room temperature for 30min, followed by three washes with TBST for 5min each. Preparing ECL mixed solution in a dark room according to the proportion of ECLA to ECLB =1 to 1, then placing the treated PVDF film with the surface facing upwards in an exposure box, adding the prepared ECL mixed solution to react for 1-2min, then discarding reaction liquid, adjusting exposure conditions according to the luminous intensity of a developing reagent, and starting exposure. The resulting film was scanned, developed for color by Photoshop, and analyzed for optical density by Alpha software.
2. Results of the experiment
The results are shown in fig. 1, and show that representative compounds selected from the present invention have a degradation effect on era protein at a concentration of 0.1 μ M compared to the positive drug fluvestant, wherein I-6 potency is comparable to the positive drug.
Claims (7)
1. A tetrahydroisoquinoline compound or pharmaceutically acceptable salt used as a dual-target compound of an estrogen receptor and histone deacetylase, has a structural formula shown as a general formula (I):
wherein:
x is H or F;
y is selected from the following structures:
2. the tetrahydroisoquinoline compound or the pharmaceutically acceptable salt thereof as the estrogen receptor and histone deacetylase double-target compound according to claim 1, which is any one of the following compounds:
3. the use of the tetrahydroisoquinoline compounds or pharmaceutically acceptable salts thereof as estrogen receptor and histone deacetylase dual-target compounds according to claim 1 in the preparation of estrogen receptor down-regulating agents.
4. The use of the tetrahydroisoquinoline compounds or pharmaceutically acceptable salts thereof as estrogen receptor and histone deacetylase dual-target compounds according to claim 1 in the preparation of histone deacetylase inhibitors.
5. The use of the tetrahydroisoquinoline compounds or pharmaceutically acceptable salts thereof as estrogen receptor and histone deacetylase dual-target compounds according to claim 1 in the preparation of medicaments for treating or preventing hormone receptor positive breast cancer and triple negative breast cancer.
6. A pharmaceutical composition, comprising a therapeutically effective amount of the tetrahydroisoquinoline compounds or pharmaceutically acceptable salts thereof as claimed in claim 1, wherein the tetrahydroisoquinoline compounds or pharmaceutically acceptable salts thereof are used as estrogen receptor and histone deacetylase dual-target compounds, and pharmaceutically acceptable excipients.
7. The method for synthesizing the tetrahydroisoquinoline compounds or pharmaceutically acceptable salts thereof as the estrogen receptor and histone deacetylase dual-target compounds according to claim 1, comprising the steps of:
(1) Heating, refluxing and demethylating the compound IA by hydrobromic acid to prepare a compound IB;
(2) Condensing the compound IB with a compound IC under the action of a condensing agent HATU to obtain a compound ID;
(3) Reducing the compound ID under the action of sodium borohydride and iodine elementary substance to obtain a compound IE;
(4) Cyclizing the compound IE and the compound IF under the alkaline condition to obtain a compound IG;
(5) Compound IG is subjected to ester hydrolysis using lithium hydroxide or hydroxamation using hydroxylamine hydrochloride to give the compound of formula I, the reaction formula is shown below:
IF is
R is
Wherein X and Y are defined as in claim 1.
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