Isoindoline compound, and preparation method, pharmaceutical composition and application thereof

A compound and prodrug technology, applied in the field of polysubstituted isoindoline compounds, can solve the problems that are still in preclinical or clinical research, and the effect of other indications is not satisfactory.

Active Publication Date: 2020-04-07
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0034] 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

Method used

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  • Isoindoline compound, and preparation method, pharmaceutical composition and application thereof
  • Isoindoline compound, and preparation method, pharmaceutical composition and application thereof
  • Isoindoline compound, and preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0480] Example 1: 3-(1-oxo-4-(5-(quinoline-4-oxo)pentyl)isoindoline-2-)piperidine-2,6-dione (1)

[0481]

[0482] 3-(4-(5-hydroxypentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (100mg, 0.303mmol, 1eq.), 4-hydroxyquinoline (132mg, 0.909mmol, 3eq.) and triphenylphosphine (159mg, 0.605mmol, 2eq.) were dissolved in 20mL dry THF, and diisopropyl azodicarboxylate (120μL, 0.605mmol, 2eq. ). The resulting mixture was stirred and reacted at room temperature for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure. The resulting residue was first separated by silica gel column chromatography, and then purified by HPLC to obtain 3-(1-oxo-4-(5-( Quinoline-4-oxo)pentyl)isoindoline-2-)piperidine-2,6-dione 52 mg, white solid, yield 38%; 1 H NMR (400MHz, DMSO) δ11.00(s, 1H), 8.71(d, J=5.2Hz, 1H), 8.12-8.07(m, 1H), 7.93(dd, J=8.4, 0.5Hz, 1H) , 7.73(ddd, J=8.4, 6.9, 1.5Hz, 1H), 7.57(dd, J=7.3, 1.3Hz, 1H), 7.55-7.51(m, 1H), 7.48(dd, J=7.5, 1.4Hz , 1H),...

Embodiment 2

[0483] Example 2: 3-(1-oxo-4-(3-(quinoline-4-oxo)propyl)isoindoline-2-)piperidine-2,6-dione (2)

[0484]

[0485] Under nitrogen protection, 3-(4-(3-hydroxypropyl)-1-oxoisoindoline-2-)piperidine-2,6-dione (48mg, 0.16mmol), 4-hydroxy Quinoline (70mg, 0.48mmol) and triphenylphosphine (84mg, 0.32mmol) were added to a 100mL round bottom flask, 20mL of tetrahydrofuran was added, and vigorously stirred. Then diisopropyl azodicarboxylate (65 mg, 0.32 mmol) was added. After the reaction was completed, the solvent was spun away, and purified by HPLC to obtain 17.6 mg of the product, with a yield of 26%; 1H NMR (400MHz, DMSO) δ10.96(s, 1H), 9.10(d, J=6.4Hz, 1H), 8.26(d, J=7.7Hz, 1H), 8.13(d, J=8.4Hz, 1H ), 8.08-8.01(m, 1H), 7.79(t, J=11.3Hz, 1H), 7.56(t, J=6.4Hz, 2H), 7.46(dd, J=10.5, 4.4Hz, 2H), 5.11 (dd, J=13.3, 5.1Hz, 1H), 4.52(t, J=5.9Hz, 2H), 4.47(d, J=17.1Hz, 1H), 4.31(d, J=17.1Hz, 1H), 3.00 -2.84(m, 3H), 2.6(m, 1H), 2.36-2.14(m, 3H), 1.97-1.86(m, 1H).

Embodiment 3

[0486] Example 3: 3-(1-oxo-4-(6-(quinoline-4-oxo)hexyl)isoindoline-2-)piperidine-2,6-dione (3)

[0487]

[0488] Replace 3-(4-(5-hydroxypentyl)-1-oxoisoindoline-2-)piperidine-2,6-dione with 3-(4-(6-hydroxyhexyl)-1 -Oxoisoindoline-2-)piperidine-2,6-dione, the preparation method is the same as 3-(1-oxo-4-(5-(quinoline-4-oxo)pentyl)isoindoline Indoline-2-)piperidine-2,6-dione, 47.2 mg, yield 50%; 1 H NMR (400MHz, DMSO) δ11.00(s, 1H), 8.72(d, J=5.3Hz, 1H), 8.14(dd, J=8.3, 0.9Hz, 1H), 7.97-7.91(m, 1H) , 7.74(ddd, J=8.4, 6.9, 1.5Hz, 1H), 7.56(tdd, J=4.7, 3.9, 1.2Hz, 2H), 7.48-7.40(m, 2H), 7.02(d, J=5.3Hz , 1H), 5.13(dd, J=13.2, 5.2Hz, 1H), 4.46(d, J=17.2Hz, 1H), 4.30(d, J=17.1Hz, 1H), 4.25(t, J=6.3Hz , 2H), 2.92(ddd, J=17.5, 13.5, 5.5Hz, 1H), 2.70-2.63(m, 2H), 2.59(dd, J=16.3, 2.0Hz, 1H), 2.41(ddd, J=26.5 , 13.4, 4.6Hz, 1H), 2.05-1.95(m, 1H), 1.92-1.83(m, 2H), 1.71-1.62(m, 2H), 1.61-1.51(m, 2H), 1.44(dt, J =15.9,8.0Hz,2H).

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Abstract

The invention relates to a polysubstituted isoindoline compound represented by a general formula (I), and a preparation method, a pharmaceutical composition and an application thereof. Specifically, as a CRL4CRBNE3 ubiquitin ligase regulator with a novel structure, the polysubstituted isoindoline compound provided by the invention has stronger anti-tumor activity and an anti-tumor spectrum, and can be used for preparing medicines for treating diseases related to CRL4CRBNE3 ubiquitin ligase.

Description

[0001] priority statement [0002] This application claims the priority of the Chinese patent application with the application number 201811156797.9, the application date is September 30, 2018, and the invention name is: "isoindoline compounds, their preparation method, pharmaceutical composition and use", here The entire contents of which are incorporated into this application by reference. [0003] 1. Technical field [0004] The present invention relates to a class of polysubstituted 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. [0005] 2. Background technology [0006] 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 regul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D401/04C07D495/04C07D413/14C07D491/107C07D498/10C07D498/20C07D471/10C07D487/10A61P35/00A61P29/00A61P25/00A61P37/00A61K31/4709A61K31/496A61K31/538A61K31/55A61K31/4545
CPCC07D401/14C07D401/04C07D495/04C07D413/14C07D491/107C07D498/10C07D498/20C07D471/10C07D487/10A61P35/00A61P29/00A61P25/00A61P37/00C07B2200/07C07D405/14C07D409/14C07D417/14C07D471/04A61K31/4545A61K31/4725A61K31/4709A61K31/5377C07D491/048C07D419/14A61K45/06
Inventor 陈小华李佳程宇周宇波聂辉军汪玉洁田洪涛阚伟娟米田胡小蓓周宾山闫克念徐高亚钟毓华冯磊
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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