Tetrahydroisoquinoline compounds as selective estrogen receptor down-regulator, synthesis method and application
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An estrogen receptor and synthesis method technology, applied in the field of its preparation and tetrahydroisoquinoline derivatives, can solve the problems of poor drug characteristics, limited effective degradation of ER, etc., and achieves low effective dose, excellent SERD activity, low Effects of security risks
Active Publication Date: 2022-02-15
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 present invention relates to the field of medicine, in particular to a tetrahydroisoquinoline derivative, its preparation method and its application in medicine. Compared with the prior art, the compound of the present invention has better SERD activity, and has the following advantages: ① The preliminary safety of the compound of the present invention is better than that of the existing tetrahydroisoquinoline SERD compounds; ② The experimental data in animals show that , at the same dose, the pharmacokinetic parameters AUC and Cmax of the compound of the present invention are significantly higher than those of the existing tetrahydroisoquinoline SERD compounds; ③ The compound of the present application has a lower hERG safety risk. It can be seen that the compound of the present invention has better PK properties, so it can be reasonably predicted that the effective dose of the compound of the present invention will be lower and the drug safety will be higher when it is used in clinical practice.
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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