Tetrahydroisoquinoline compound used as selective estrogen receptor down-regulation agent, synthetic method and application
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A technology of estrogen receptors and compounds, which is applied in the field of medicine, can solve the problems of poor drug properties and restrictions on the effective degradation of ER
Active Publication Date: 2020-10-27
SHANGHAI XUNHE PHARMA TECH CO LTD
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[0005] Fulvestrant is currently the only SERD drug approved for clinical use in the treatment of ER+ breast cancer, but it has poor druggability, rapid metabolism and must be administered by monthly intramuscular injections, unlike those seen in in vitro studies It limits the efficient degradation of ER compared to complete ER degradation (~50% ER degradation in clinical samples)
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Embodiment 1～16
[0065] The synthesis of embodiment 1~16:I-1
[0066] synthetic route:
[0067]
[0068] step 1:
[0069] Compound IA-1 (2.28g, 0.01mol), IB-1 (2.24g, 0.01mol) was added to 1,4-dioxane (40mL), and then N,N-diisopropylethylamine (DIPEA , 3.87g, 0.03mol), the reaction system was stirred at 80°C for 12h. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether 1 / 1) to obtain the target product IC-1 (1.36 g, yield 45%). LCMS: MS Calcd.: 302.4, MS Found: 303.2 [M+1].
[0070] Step 2:
[0071] Compound IC-1 (500mg, 1.65mmol), ID-1 (411mg, 1.82mmol) and acetic acid (500mg, 8.3mmol) were added to toluene (10mL), under the protection of nitrogen, the reaction system was heated to 80°C and stirred for 12h. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: ethyl a...
Embodiment 17-40
[0081] synthetic route:
[0082]
[0083] step 1:
[0084] Compound IA-1 (2.28g, 0.01mol), IB-1 (2.24g, 0.01mol) was added to 1,4-dioxane (40mL), and then N,N-diisopropylethylamine (DIPEA , 3.87g, 0.03mol), the reaction system was stirred at 80°C for 12h. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether 1 / 1) to obtain the target product IC-1 (1.36 g, yield 45%). LCMS: MS Calcd.: 302.4, MS Found: 303.2 [M+1].
[0085] Step 2:
[0086] Compound IC-1 (500mg, 1.65mmol), IF-1 (383mg, 1.82mmol) and acetic acid (500mg, 8.3mmol) were added to toluene (10mL), under the protection of nitrogen, the reaction system was heated to 80°C and stirred for 12h. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether 1 / 3) to obtain the targe...
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Abstract
The invention relates to the field of medicine, in particular to a tetrahydroisoquinoline derivative and a preparation method and medical application thereof. Compared with the prior art, the compoundprovided by the invention has better SERD activity and also has the following advantages: (1) the initial safety of the compound provided by the invention is superior to that of the existing tetrahydroisoquinoline SERD compound; (2) animal in-vivo experimental data show that the pharmacokinetic parameters AUC and Cmax of the compound disclosed by the invention are obviously higher than those of the existing tetrahydroisoquinoline SERD compound under the same dosage; and (3) the compound provided by the invention has relatively low hERG safety risk. Therefore, the compound disclosed by the invention has better PK property, so that reasonable prediction can be realized, the effective dose of the compound is lower when the compound is applied to clinical use, and the medication safety is higher.
Description
technical field [0001] The invention belongs to the field of medicine, and in particular relates to a tetrahydroisoquinoline derivative, its preparation method and its application in medicine. Background technique [0002] The estrogen receptor (ER) is a transcriptional regulatory protein that mediates ligand activation induced by a variety of biological effects through its interaction with endogenous estrogens. ER contains two isoforms: ER encoded by different genes α and ER β . ER α and ER β High similarity is shown at the amino acid level, the similarity in the DNA binding domain is as high as 97%, and the similarity in the ligand binding domain is as high as 56%. However, there is only a low homology of 24% in the N-terminus. ER contains 6 structural domains (A-F), which consist of 4 main functional regions. The functional region of the N-terminal A / B domain has a ligand-independent transcriptional activation functional region AF-1, and AF-1 has constitutive activat...
Claims
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