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Compounds based on crbn ligand-induced degradation of parp-1 and preparation methods and applications

A PARP-1, compound technology, applied in the field of pharmaceutical compound synthesis, can solve problems such as side effects

Active Publication Date: 2021-04-09
ZHEJIANG ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the inhibition of PARP-1 often requires the drug to be maintained at a high concentration for a long time, which may cause serious side effects

Method used

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  • Compounds based on crbn ligand-induced degradation of parp-1 and preparation methods and applications
  • Compounds based on crbn ligand-induced degradation of parp-1 and preparation methods and applications
  • Compounds based on crbn ligand-induced degradation of parp-1 and preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] (1) Preparation of 8-amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoisoin-4-yl)octamide (2-1):

[0050]

[0051] Add lenalidomide (10mmol) and 8-((tert-butoxycarbonyl)amino)octanoic acid (10mmol) into a 50mL round bottom flask, add 10mL of anhydrous DMF (N,N-dimethylformamide) to dissolve, Then HATU (10.5mmol, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate) and TEA (10.5mmol, triethylamine) were added, The reaction was carried out at room temperature 25° C. for 12 hours under the protection of nitrogen. After the reaction is complete, pour the reaction solution into water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain an unpurified white crude product; take 1.0 mmol of the above crude product and add 3 mL of TFA (Trifluoroacetic acid) and DCM (dichloromethane) mixed solvent TFA / DCM (1:5, v / v), reacted at room temperature 25 °...

Embodiment 2

[0057] Preparation of N-(11-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoisoin-4-yl)amino)-11-oxoisopentenyl)- 2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide (1-2). Referring to Example 1 for the specific preparation method, it is only necessary to replace the 8-((tert-butoxycarbonyl)amino)octanoic acid in Example 1 with 11-((tert-butoxycarbonyl)amino)undecanoic acid. 1-2 Its structure is as follows:

[0058]

[0059] The characterization results are as follows: 1 H NMR(500MHz,DMSO-d6)δ12.62(s,1H),11.05(s,1H),9.78(s,1H),8.28(d,J=7.8Hz,1H),8.25(s,1H) ,7.97(d,J=7.9Hz,1H),7.89(t,J=8.3Hz,1H),7.83(t,J=8.2Hz,2H),7.55(d,J=6.8Hz,1H),7.51 (d,J=5.3Hz,1H),7.47–7.42(m,1H),7.23–7.17(m,1H),5.18(dd,J=13.3,5.1Hz,1H),4.33(s,2H), 3.40(s,3H),3.22(dd,J=13.0,6.7Hz,2H),2.99–2.90(m,1H),2.63(d,J=17.0Hz,1H),2.36(d,J=7.6Hz ,2H),2.00(s,1H),1.63–1.46(m,4H),1.28(d,J=15.4Hz,12H).13C NMR(126MHz,DMSO-d6)δ173.33,171.88,171.55,168.33,163.89 ,159.87,157.29,145.40,134.77,134.29,134.12,133.95,13...

Embodiment 3

[0061]Preparation of N-(12-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoisoin-4-yl)amino)-12-oxodecyl)-2- Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide (1-3). Referring to Example 1 for the specific preparation method, it is only necessary to replace the 8-((tert-butoxycarbonyl)amino)octanoic acid in Example 1 with 12-((tert-butoxycarbonyl)amino)dodecanoic acid. Its structure is as follows:

[0062]

[0063] The characterization results are as follows: 1 H NMR (500MHz, DMSO-d6) δ12.61(s, 1H), 11.04(s, 1H), 9.77(s, 1H), 8.27(d, J=7.8Hz, 1H), 8.24(t, J= 4.7Hz, 1H), 7.97(d, J=7.9Hz, 1H), 7.88(t, J=7.6Hz, 1H), 7.86–7.78(m, 2H), 7.54(dd, J=6.8, 2.3Hz, 1H),7.51–7.50(m,1H),7.47–7.41(m,1H),7.25–7.14(m,1H),5.16(dd,J=13.3,5.1Hz,1H),4.33(s,2H) ,3.37(s,4H),3.20(dd,J=13.0,6.7Hz,2H),2.98–2.88(m,1H),2.62(d,J=16.9Hz,1H),2.37–2.34(m,2H ),1.63–1.45(m,4H),1.31–1.23(m,14H).13C NMR(126MHz,DMSO-d6)δ173.33,171.87,171.55,168.32,163.88,159.86,157.27,145.41,134.77,134.23,13 ,133.97,133...

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Abstract

The invention discloses a compound based on CRBN ligand-induced degradation of PARP‑1, its preparation method and application, which is obtained by linking PARP‑1 small molecule inhibitors with cereblon protein ligands in E3 ubiquitin ligase complexes by using linking chains Bifunctional small molecules. The invention also discloses the preparation method of the compound, the pharmaceutical composition of the compound, and the application of the compound and the pharmaceutical composition in the preparation of drugs for preventing or / and treating cancer. The compound can induce the degradation of PARP-1 with only a small dosage, which can reduce the toxic and side effects on the human body; it can also show excellent PARP-1 degradation and anticancer activity, and its anticancer effect is better than that of PARP-1 inhibition Agents can be used to prevent or / and treat various cancers, and have great application prospects in the field of medicine.

Description

technical field [0001] The invention relates to the field of pharmaceutical compound synthesis, in particular to a compound based on CRBN ligand-induced degradation of PARP-1, its preparation method and application. Background technique [0002] Cereblon is a protein encoded by the human CRBN gene, and the CRBN homologs are highly conserved, suggesting its importance in physiology. Cereblon forms the E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDBl), Cullin-4A (CUL4A) and Cullin-1 regulator (ROCI), which can ubiquitinate a series of proteins, but the specific mechanism is not yet clear. clear. Cereblon ubiquitination of target proteins resulted in an increase in fibroblast growth factor 8 (FGFB) and fibroblast growth factor 10 (FGF10), indicating that the ubiquitinase complex is important for embryonic limb growth. [0003] Studies have shown that lenalidomide has multiple effects such as anti-tumor, immune regulation and anti-angiogenesis, and lenalido...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14A61P35/00A61P35/02A61K31/502
CPCA61P35/00A61P35/02C07D401/14
Inventor 张智敏沈正荣黄文海曾申昕章迟啸马臻梁美好王尊元
Owner ZHEJIANG ACAD OF MEDICAL SCI