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Isoindoline compound as well as preparation method, pharmaceutical composition and application thereof
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A compound and prodrug technology, applied in the field of isoindoline compounds, can solve problems such as unsatisfactory effects of other indications and still in preclinical or clinical research
Active Publication Date: 2020-06-16
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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[0027] In summary, lenalidomide is mainly used for the treatment of multiple myeloma and myelodysplastic syndrome, and the effect on other indications is not satisfactory; other above-mentioned compounds such as CC-122, CC-885 and CC -220 is still in preclinical or clinical research
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Embodiment 1
[0284] Example 1: 3-(4-((1-benzyl-1H-1,2,3-triazole-4-)methoxy)-1-oxoisoindoline-2-)piperidine- 2,6-Diketone(1)
[0285] Using benzyl azide and intermediate 6 as raw materials, through synthetic route 1, the preparation method is as follows:
[0286]
[0287] mg, 0.0268mmol, 0.2equiv.) was dissolved in a mixed solution of dimethylsulfoxide-water (v / v=4:1, 5mL), and diisopropylethylamine (22μL, 0.134 mmol, 1 equiv.), after the reaction solution is mixed evenly, add sodium ascorbate (13mg, 0.067mmol, 0.5eq), continue to stir and react for 1 minute, add tris[(1-benzyl-1H-1,2 ,3-triazol-4-yl)methyl]amine (TBTA, 7mg, 0.0134mmol), the resulting reaction solution was stirred at room temperature for 30 minutes. After completion of the reaction, add water and copperion adsorbent (CupriSorb) to the reaction mixture, extract the reaction mixture with ethyl acetate, wash the organic phase with saturated ammoniumchloride and saturated sodiumchloride solution, dry over anhydrous sod...
Embodiment 2
[0288] Example 2: 3-(1-oxo-4-((1-(pyridine-4-methyl)-1H-1,2,3-triazole-4-)methoxy)isoindoline- 2-)piperidine-2,6-dione (2)
[0289]
[0290] -2,6-dione 23.7mg, yield 12%; 1 H NMR (400MHz, DMSO) δ10.96(s, 1H), 8.56(d, J=5.7Hz, 2H), 8.38(s, 1H), 7.55–7.48(m, 1H), 7.45(d, J= 7.9Hz, 1H), 7.34(d, J=7.2Hz, 1H), 7.19(d, J=5.7Hz, 2H), 5.70(s, 2H), 5.33(s, 2H), 5.10(dd, J= 13.3,5.1Hz,1H),4.35(d,J=17.5Hz,1H),4.19(d,J=17.4Hz,1H),2.90(ddd,J=17.4,13.8,5.4Hz,1H),2.58( d, J=2.3Hz, 1H), 2.47–2.34(m, 1H), 2.01–1.88(m, 1H). UPLC-MS (ESI) theoretical value is C 22 h 20 N 6 o 4 [M+H] + :433.16, the measured value is 433.30.
Embodiment 3
[0291] Example 3: 3-(1-oxo-4-((1-(pyridine-3-methyl)-1H-1,2,3-triazole-4-)methoxy)isoindoline- 2-)piperidine-2,6-dione(3)
[0292]
[0293] 29.2mg, yield 17%; 1 H NMR(400MHz,DMSO)δ10.96(s,1H),8.61(d,J=1.7Hz,1H),8.55(dd,J=4.7,1.2Hz,1H),8.38(s,1H),7.73 (dt,J=7.7,1.7Hz,1H),7.53–7.47(m,1H),7.43(d,J=8.8Hz,1H),7.42–7.38(m,1H),7.34(d,J=7.2 Hz,1H),5.68(s,2H),5.30(s,2H),5.09(dd,J=13.3,5.1Hz,1H),4.34(d,J=17.4Hz,1H),4.18(d,J =17.4Hz,1H),2.90(ddd,J=17.7,13.7,5.4Hz,1H),2.59(s,1H),2.41(qd,J=13.3,4.4Hz,1H),2.01–1.91(m, 1H). UPLC-MS (ESI) theoretical value is C 22 h 20 N 6 o 4 [M+H] + :433.15, the measured value is 433.30.
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Abstract
The invention relates to an isoindoline compound which can be used as a CRBN regulator and is shown as a general formula (I) which is described in the specification, and a preparation method, a pharmaceutical composition and an application thereof. Specifically, the polysubstituted isoindoline compound provided by the invention, as a CRL4CRBNE3 ubiquitin ligase regulator with a novel structure, has very good anti-tumor activity and immunomodulatory activity, and can be used for preparing medicines for treating diseases related to CRL4CRBNE3 ubiquitin ligase.
Description
technical field [0001] The invention relates to a class of isoindoline compounds with novel structures, their pharmaceutically acceptable salts, solvates, pharmaceutical compositions and their application in the preparation of medicines for treating or preventing various diseases. Background technique [0002] The tight regulation of protein expression in cells plays an important role in cell function, cell survival and division, and many primary or acquired diseases often involve abnormal protein function. The traditional method of regulating protein dysfunction is mainly to design targeted inhibitors or agonists, and these targeted drugs play an important role in the treatment of diseases. Nevertheless, in order to obtain a satisfactory therapeutic effect, these inhibitors or agonists usually need to be maintained at a relatively high drug concentration to achieve an effective therapeutic effect, which also leads to adverse drug reactions to a certain extent. Another way ...
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