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Fused pyrimidines as inhibitors of p97 complex

A technology for fused pyrimidine and compounds, which is applied in the field of fused pyrimidine compounds and can solve the problems of small toxicity

Active Publication Date: 2017-02-22
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Given that p97 is implicated in ERAD and IlcB turnover, but otherwise has a more restricted role in the UPS than the proteasome itself, drugs targeting p97 could retain most of the efficacy of bortezomib but with less toxicity

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  • Fused pyrimidines as inhibitors of p97 complex
  • Fused pyrimidines as inhibitors of p97 complex
  • Fused pyrimidines as inhibitors of p97 complex

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preparation example Construction

[2849] Preparation of compounds may involve protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th Edition, Wiley & Sons, 2006 and Jerry March, Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, Publishers, New York, 1992, which is incorporated herein by reference in its entirety.

[2850] Fused pyrimidine backbones can be prepared by literature methods cited hereinafter. The following schemes depict established known syntheses for these scaffolds.

[2851] Het moieties and amine substituents of fused pyrimidine backbones can be synthesized and attached to these backbones by literature methods cited hereinafter. The following schemes depict known techniques for accomplishing this connection.

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Abstract

The present invention is directed to certain fused pyrimidines having a homo or hetero cyclopentyl, cyclohexyl or cycloheptyl ring as the pyrimidine fusion partner; having an amino benzyl or substituted amino benzyl group at the 4 position of the pyrimidine ring; and a 5:6 heterobicyclo ring with at least one N, O or S at the 2 position of the pyrimidine ring. These compounds are useful for treatment of cancer by inhibition of the p97 complex.

Description

[0001] Background of the invention [0002] The AAA (ATPase associated with multiple activities) ATPase p97 with the descriptive name Valorin-containing protein is conserved in all eukaryotes and is a budding yeast (Giaever, G. et al. Nature (2002) 418, 387-391) and for life in mice (Muller, J.M. et al. Biochem. Biophys. Res. Commun. (2007) 354, 459-465). Humans with reduced-function p97 alleles suffer from syndromes including inclusion body myopathy and frontotemporal lobar degeneration (Weihl, C. et al. Hum. Mol. Genet. (2006) 15, 189-199). Loss-of-function studies in model organisms have shown that p97 plays a key role in a wide range of cellular processes including: Golgi membrane reassembly (Rabouille, C. et al. Cell (1995) 82, 905-914), membrane translocation (Ye , Y. et al. Nature (2001) 414, 652-656; Ye, Y. et al. Nature (2004) 429, 841-847), degradation of misfolded membranes and secretion via the ubiquitin-proteasome system (UPS) Protein (Golbik, R. et al. Biol. Chem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04C07D471/04C07D491/048C07D491/052A61K31/517A61K31/519A61P35/00
CPCC07D471/04C07D491/048C07D491/052C07D403/04A61P1/04A61P1/12A61P1/16A61P1/18A61P11/00A61P11/06A61P13/02A61P13/12A61P17/02A61P17/06A61P19/00A61P19/02A61P21/04A61P25/00A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P31/00A61P33/02A61P33/04A61P33/06A61P35/00A61P35/02A61P3/06A61P37/02A61P37/06A61P37/08A61P43/00A61P5/14A61P7/00A61P9/00A61P9/04A61P9/10A61P3/10A61K31/517A61K31/519
Inventor 周汉杰大卫·乌斯特罗
Owner CLEAVE BIOSCI