CN115894485A - Heteroaryl piperidine derivative, preparation method and application thereof in medicine - Google Patents
Heteroaryl piperidine derivative, preparation method and application thereof in medicine Download PDFInfo
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Abstract
The invention relates to heteroaryl piperidine derivatives, a preparation method and application thereof in medicines. Specifically, the invention provides a heteroaryl piperidine compound shown as a formula I, a pharmaceutically acceptable salt or a stereoisomer thereof and a preparation method thereof. The invention also provides a pharmaceutical composition containing the compound I, and application of the compound I and the pharmaceutical composition thereof in preparing medicaments for preventing or treating estrogen receptor-related diseases, in particular application in preparing medicaments for preventing or treating cancers.
Description
Technical Field
The invention relates to a heteroaryl piperidine derivative, a preparation method thereof and application of the heteroaryl piperidine derivative serving as an estrogen receptor modulator in preventing and/or treating estrogen receptor-mediated or dependent diseases or symptoms.
Background
Estrogen receptors include two broad classes: one is the classical nuclear receptor, including ER α and ER β, which are located in the nucleus and mediate the estrogenic genotypic effects, i.e., exert a "genotypic" regulatory effect by regulating the transcription of specific target genes; the second is the membrane receptor, which includes the membrane components of the classical nuclear receptor, as well as GPER1 (GPR 30), gaq-ER and ER-X, which belong to the G-protein coupled receptor family. Long-term hyperstimulation of estrogen, increased expression level of era or enhanced transcriptional activation activity are important factors leading to breast cancer.
Approximately 70% of breast cancers express ER α, which makes it a major target for the treatment of breast cancer. Current standard of care treatment for ER-positive breast cancer patients includes three broad classes of drugs: (1) Drugs directed against ER α, such as selective estrogen receptor down-regulators (SERDs), selective Estrogen Receptor Modulators (SERMs), and Selective Estrogen Receptor Covalent Antagonists (SERCAs); (2) Aromatase Inhibitors (AIs) which reduce estrogen levels, (3) CDK4/6 kinase inhibitors. Wherein the binding of SERDs to estrogen receptors not only antagonizes the activity of estrogen receptors, but also promotes the degradation of receptors.
The Chinese patent with the application number of CN201580069484.8 discloses an estrogen receptor modulator, which comprises the following compound 340 and compound 277, wherein the compound 340 is GDC-9545.GDC-9545 is a potent estrogen receptor degrader and is currently in clinical trials.
Compound 340 (GDC-9545) Compound 277
Because of the relatively few estrogen receptor modulators currently on the market, there is a need to develop more estrogen receptor degrading drugs that can be used to treat breast cancer or other estrogen receptor related diseases.
Disclosure of Invention
The invention provides a brand-new estrogen receptor modulator, a preparation method thereof and application thereof in preparing medicaments for preventing or treating estrogen receptor related diseases.
The technical scheme of the invention is as follows:
the invention provides a compound shown in a formula I, and pharmaceutically acceptable salt or stereoisomer thereof,
I。
in some embodiments, the stereoisomer has the structure shown in formula I-1,
I -1
the invention also provides a pharmaceutical composition, which comprises the compound I, pharmaceutically acceptable salts or stereoisomers thereof and a pharmaceutically acceptable carrier. The carrier includes adjuvant ingredients conventional in the art, such as, for example, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, and wetting agents, and the like.
The pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquid, suspension, granules, powder, fine granules, pills, mini-tablets, instant films, nasal spray, transdermal patches, injections or various sustained and controlled release preparations and the like. The pharmaceutical compositions may be administered orally, transmucosally, rectally, or parenterally (including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally), preferably orally. The administration dose may be appropriately adjusted depending on the age, sex and type of disease of the patient.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or solution. The pharmaceutical compositions are preferably prepared in dosage unit form containing specific amounts of the active ingredient. For example, the pharmaceutical composition may be provided in a tablet or capsule containing from about 0.1 to 1000mg, preferably from about 0.25 to 250mg, and more preferably from about 0.5 to 100mg of the active ingredient. Suitable daily dosages for humans or other mammals may vary widely depending on the condition of the patient and other factors, but can be determined using conventional methods.
The invention also provides a preparation method of the compound I-1 or the pharmaceutically acceptable salt thereof, which comprises the following steps:
the invention also provides application of the compound I or I-1, pharmaceutically acceptable salts or stereoisomers thereof, or a pharmaceutical composition thereof in preparing a medicament for preventing or treating estrogen receptor-related diseases. The estrogen receptor-related diseases include ER- α dysfunction associated with cancer (bone cancer, breast cancer, lung cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, and uterine cancer), central nervous system defects (e.g., alcoholism, migraine, etc.), cardiovascular system defects (e.g., aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular diseases, coronary artery diseases, hypertension, etc.), blood system defects, immune and inflammatory diseases, metabolic defects (e.g., cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis, etc.), neurological defects (e.g., alzheimer's disease, parkinson's disease, migraine, vertigo, etc.), mental defects (e.g., anorexia nervosa, attention deficit hyperactivity disorder, dementia, major depressive disorder, psychosis, etc.), or reproductive defects (e.g., menstrual onset age, endometriosis, infertility), and the like.
The invention also provides application of the compound I or I-1, pharmaceutically acceptable salts or stereoisomers thereof, or a pharmaceutical composition thereof in preparing a medicament for treating cancer. The cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer or uterine cancer; preferably breast cancer. The breast cancer is preferably estrogen receptor positive breast cancer.
The compounds provided by the invention can be used for treating breast cancer alone or in combination with other medicines for treating breast cancer. Such other drugs include, but are not limited to, aromatase inhibitors, anthracyclines, platins, nitrogen mustard alkylating agents, taxanes. Exemplary drugs for treating breast cancer include, but are not limited to, taselisib (GDC-0032), paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab, pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine, or ixabepilone.
The compound I or I-1, the pharmaceutically acceptable salt or the stereoisomer thereof or the pharmaceutical composition thereof provided by the invention has better degradation activity on ER alpha as a selective estrogen receptor degradation agent, and can well inhibit the proliferation of breast cancer cells.
Detailed Description
The present invention will be further illustrated with reference to specific examples and test examples, but the scope of the present invention is not limited in any way.
Definitions and explanations
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Examples of the pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts, and also include salts of amino acids (such as arginine and the like), and salts of organic acids such as glucuronic acid and the like. Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, the salt is prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two.
Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to afford the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished using chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The present invention is intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include atoms of the same atomic number but different mass numbers. As a general example and not by way of limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon including 13 C and 14 C. isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically-labeled reagent in place of the non-labeled reagent additionally employed.
The compounds were named either manually or by ChemDraw software, and the commercially available compounds were given the supplier catalog name.
Example 1: synthesis of Compound I-1
To a mixture of (R) -1- (1H-indol-3-yl) -N- (2,2,2-trifluoroethyl) propan-2-amine (1.5 g,5.9 mmol,1 eq), 2,6-difluoro-4-hydroxybenzaldehyde (1.1 g,6.4 mmol,1.1 eq), and acetic acid (10 mL) in toluene (100 mL) at room temperature was stirred a mixture of 16H at 100 ℃. After cooling to room temperature, the mixture was concentrated, the residue was washed with aqueous sodium bicarbonate solution, extracted with DCM, washed with brine, dried over anhydrous sodium sulfate and concentrated, and the residue was purified by column chromatography (PE/EA = 5/1) to give compound 2 (2.0 g, yield 87%) as a yellow solid. MS m/z (ESI): 397.1 [ M +1].
A mixture of compound 2 (2.0 g,7.9 mmol,1.0 eq), tert-butyl-3-aminoazetidine-1-carboxylic acid ester (2.1 g,5.1 mmol,1.5 eq), cesium carbonate (4.9 g,15.2 mmol,3.0 eq) in DMF (100 mL) was stirred at 90 ℃ under nitrogen for 30 min. The mixture was cooled to room temperature, extracted with DCM, washed with brine, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by flash column chromatography (PE/EA = 4/1) to give compound 3 (2.4 g, yield 86%) as a yellow solid. MS m/z (ESI): 552.2 [ M +1].
To a solution mixture of Compound 3 (2.4 g,4.4 mmol,1.0 eq) in dioxane (100 mL) at 0 deg.C was added H 2 SO 4 (2.5 mL,4.4 mmol,1.0 eq) and the mixture was stirred at room temperature for 2 h. Aqueous NaOH (1.0M) was added to the mixture to pH = 8-9, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated to give compound 4 (1.6 g, yield 80%) as a yellow solid. MS m/z (ESI): 452.2 [ M +1]]。
A solution of compound 4 (1.6 g,3.5 mmol,1 eq), (2-bromoethyl) 4,4,5,5,5-pentafluoropentyl) sulfide (1.3 g,4.3 mmol,1.2 eq) and potassium carbonate (966 mg,7.0 mmol,2.0 eq) in acetonitrile (100 mL) was stirred at room temperature overnight. The mixture was concentrated and the resulting residue was purified by flash column chromatography (DCM/MeOH = 10/1) to give compound 5 (960 mg, 40% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.59 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.04-6.94 (m, 2H), 6.68 (d, J = 10.4 Hz, 2H), 5.24 (s, 1H), 4.46-4.58 (m, 2H), 4.24-4.17 (m, 2H), 3.66-3.58 (m, 2H), 3.41-2.51 (m, 8H), 2.46-2.36 (m, 2H),2..01-1.89 (m, 2H), 1.31-1.20 (m, 2H), 1.06 (d, J = 6.8 Hz, 3H). MS m/z（ESI）：672.2 [M+1]。
To a mixture of compound 5 (960 mg,1.4 mmol,1.0 eq) in ethyl acetate/acetic acid (100 mL, v/v 15/1) was added hydrogen peroxide (476 mg,14 mmol, 10)eq, 30%), the mixture was stirred at room temperature for 4 h. The mixture was washed with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried and concentrated. The resulting residue was purified by column chromatography (DCM/MeOH = 10/1) to give compound I-1 (100 mg, yield 10%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.04-6.94 (m, 2H), 6.68 (d, J = 10.4 Hz, 2H), 5.24 (s, 1H), 4.46-4.58 (m, 2H), 4.24-4.17 (m, 2H), 3.66-3.58 (m, 2H), 3.42-2.52 (m, 8H), 2.46-2.36 (m, 2H),2..01-1.89 (m, 2H), 1.31-1.21 (m, 2H), 1.08 (d, J = 6.8 Hz, 3H). MS m/z（ESI）：688.2 [M+1]。
Test example 1 degradation of ER. Alpha. Protein by Compound I-1
1. Purpose of the experiment
Determination of the degradation of ER α protein by Compound I-1 according to DC 50 And maximum degradation efficiency E max The compounds were evaluated for in vitro degradation activity.
2. Test method
MCF-7 cells (ATCC, HTB-22) were cultured in 88% RPMI 1640 (Invitrogen, 22400-089) medium containing 10% FBS (ExCell Bio, FSP 500), 1% P/S (Hyclone, SV 30010), 1% Gl μ taMax (Invitrogen, 25030-061). The first day of experiment, after centrifugation, digestion and cell collection, the cell suspension concentration was adjusted to 8.75X 10 4 40. Mu.L of suspension per well in 384-well plates (Greiner, 781090) at 37 ℃ in 5% CO 2 The incubator was overnight. The next day, compounds were formulated in 10 mM stock in 100% DMSO and diluted to 2.5 μ M (5X) in 1640 complete medium followed by a 4-fold concentration gradient dilution for 10 concentration points. 1 μ M fulvestrant was used as Low Control (LC) and 0.5% DMSO as High Control (HC). Adding 10 μ L of the corresponding compound to each well of 384-well plate, 37 deg.C, 5% CO 2 Incubate in incubator for 24 hours. On the third day, 50. Mu.L of 8% paraformaldehyde (EM Sciences, 15710-S) was added to each well of the 384-well plate, and fixed at room temperature for 40 minutes; add 100. Mu.L PBS per well and wash 2 times, followed by 50. Mu.L 0.1% Triton X-100 per well (Sigma, T9284)) Standing at room temperature for 15 minutes; the plates were washed 5 times with PBS, and then 50. Mu.L of blocking solution containing 0.1% Tween 20 (Sigma, P1379) was added to each well and allowed to stand at room temperature for 1 hour; the plate was aspirated, and primary antibody (Estrogen Receptor α (D8H 8) rabbitmab, cell Signal, 8644S) was added at a rate of 1:1000, 25. Mu.L per well were added and incubated overnight at 4 ℃. On the fourth day, the plates were washed 5 times, and then secondary antibodies (IRDye 800CW Goat anti-Rabbit, licor,926-32211,1, 1000) were diluted with DRAQ5 (Cell Signal,4084L, 1; the plate was washed 5 times and the signal values at 800 nm, 700nm were read in the Odyssey imaging system, respectively. The Inhibition rate was calculated by Ratio (800 nm/700 nm), i.e.,% Inhibition = (Assay well-Average _ HC)/(Average _ LC-Average _ HC) × 100%, and DC was calculated by fitting a dose-effect curve using "log (Inhibition) vs. response- -Variable slope" in Prism 5 50 (ii) a Maximum degradation rate of compound E max Is the percentage of the level of ER α remaining in cells after 500 nM treatment to the level of ER α after 1000 nM fulvestrant treatment.
3. Test results
Degradation activity of compounds on ER α was determined by In-Cell-Western assay, DC 50 And E max See table 1.
TABLE 1 degradation of ER alpha protein by Compounds
And (4) conclusion: the compound I-1 of the invention has better degradation activity on ER alpha than the compound 277 disclosed in GDC-9545 and CN 201580069484.8.
Test example 2 inhibition of MCF-7 cell proliferation by Compound I-1
1. Purpose of experiment
Determination of the inhibitory Effect of Compound I-1 on the in vitro proliferation of MCF-7 cells, according to IC 50 The activity of the compounds was evaluated.
2. Experimental methods
MCF-7 cells (ATCC, HTB-22) were cultured in medium (Gibco, 22400089) containing 10% fetal bovine serum (Hyclone, SV 30087.03), 1% by volume PS (penicillin-streptomycin diabody, gibco, 15070063) and 1% by volume Gl μ tamax (Gibco, 35050061) 1640. On the first day of the experiment, after centrifugation, digestion, and cell collection, the cell concentration was adjusted with complete medium, seeded in 384-well plates (Greiner-781091) at a cell density of 600 cells/well, 40. Mu.L of cell suspension per well, and the plates were placed at 37 ℃ with 5% CO 2 The incubator was overnight. The next day, compounds were formulated into 10 mM stocks in 100% DMSO and further diluted to 5 μ M (10X) in 1640 medium followed by 4-fold concentration gradient dilutions for 8 concentration points. 2 μ M fulvestrant was used as Low Control (LC) and 0.5% DMSO as High Control (HC). Adding 10 μ L of corresponding compound into 384-well plate at 37 deg.C and 5% CO 2 Culturing in an incubator for 6 days. On the eighth day, 25. Mu.L CellTiter-Glo (Promega, G7573) was added to each well of the plate, and after incubation at 400 rpm for 10 minutes at room temperature, luminescence signals were read in Envision (Perkinelmer). The Inhibition rate was calculated by fitting a dose-effect curve to% Inhibition = (Assay well-Average _ HC)/(Average _ LC-Average _ HC) × 100%, using Prism 5' log (inhibitor) vs. response — Variable slope ″, and calculating IC 50 。
3. Measurement results
The proliferation inhibiting effect of the compound on MCF-7 cells is determined by detecting ATP content in living cells through CellTiter-Glo, and the detected IC 50 See table 2.
TABLE 2 inhibition of MCF-7 cell proliferation by compounds
And (4) conclusion: compared with the compound 277 disclosed by GDC-9545 and CN201580069484.8, the compound I-1 disclosed by the invention has better inhibition effect on the proliferation of MCF-7 cells.
Test example 3 evaluation of Permeability and transporter substrates
Cell: caco-2 cells
The instrument comprises the following steps: water purification, ELGA LabWate; biological safety cabinet, nuaire; constant temperature CO 2 Incubator, thermo; microplate reader, perkinElmer; LC-MS/MS, AB SCIEX.
The method comprises the following steps: the objective of this study was to determine the bidirectional permeability of compounds using the Caco-2 monolayer model and to assess whether they are transported by P-glycoprotein (P-gp) efflux. In the experiment, caco-2 cells were seeded in a 96-well cell plate and used for transport experiments after continuous culture for 24 days. The compounds were administered in both directions with and without verapamil at a concentration of 2.00 μ M. After 120 minutes of incubation, samples of the top end A and the base end B are collected, and the content of the test sample in each sample is detected by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. And calculating the apparent permeability coefficient and the efflux rate. The data are summarized in Table 3.
TABLE 3 results of Permeability experiments
* Namely compound 277 disclosed in CN201580069484.8
And (4) conclusion: the compound I-1 disclosed by the invention shows medium permeability in Caco-2 cells, has low efflux rate, and is remarkably superior to the compound 277 disclosed by GDC-9545 and CN 201580069484.8.
Claims (10)
1. A compound of formula I, a pharmaceutically acceptable salt or a stereoisomer thereof,
2. the compound of claim 1, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein the stereoisomer has a structure represented by formula I-1,
3. a process for preparing a compound of claim 2, or a pharmaceutically acceptable salt thereof, comprising the steps of:
4. a pharmaceutical composition comprising a compound of any one of claims 1-2, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
5. Use of a compound according to any one of claims 1-2, a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the prophylaxis or treatment of a disorder associated with an estrogen receptor.
6. Use of a compound according to any one of claims 1 to 2, a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the treatment of cancer.
7. The use of claim 6, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, or prostate cancer.
8. The use of claim 7, wherein the cancer is breast cancer.
9. The use of claim 8, wherein the breast cancer is estrogen receptor positive breast cancer.
10. The use according to any one of claims 8 or 9, further comprising an additional drug selected from taselisib, paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab, pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine or ixabepilone.
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| CN110139863A (en) * | 2016-10-28 | 2019-08-16 | 罗欣药业(上海)有限公司 | Indoles and substituted piperidines as estrogen receptor degradation agent |
| CN114748480A (en) * | 2021-01-08 | 2022-07-15 | 轩竹生物科技股份有限公司 | Pharmaceutical composition for preventing and/or treating cancer |
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| CN107108611A (en) * | 2014-12-18 | 2017-08-29 | 豪夫迈·罗氏有限公司 | Tetrahydropyridine simultaneously [3,4 b] indoles estrogenic agents and application thereof |
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