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Publication Number
US-10174005-B2
Publication Date
2019-01-08
Expiration Date
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.
Core Innovation
The invention relates to fused pyrimidine compounds of Formula IA and Formula IB, including pharmaceutically acceptable salts and pharmaceutical compositions. Structural definitions include A being N5 or O, HET being a 5:6 bicyclic aromatic group selected from Formula H5 or Formula H10, and substituent definitions including R1, R5, R6, R7, and Ar being phenyl or fluorophenyl.
The disclosure further provides Formula IA1 and Formula IB1 compounds with A being NH or O, R1 being CO2H or CONH2, R6 being methyl or methoxy, and Ar being phenyl or fluorophenyl. The biological and medical description centers on inhibition of Valosin Containing Protein-Proteosome pathway activity, including p97 inhibition by binding to the p97 active site, and the compounds and pharmaceutical compositions are intended for treating cancer or neoplastic malconditions.
The document also reports synthetic routes and transformations for fused pyrimidine intermediates and final compounds, including annulated heterocycle carboxamide or nitrile-containing structures, conversion of nitriles to carboxamides or methylamines, ester-to-acid or ester-to-amide conversions, and additional derivatizations through aldehyde intermediates. Selected intermediates and final compounds are reported with yields, LCMS or LRMS, HPLC purity, and 1H NMR, and the biological characterization includes p97 proteasome-focused assays and ADME-style tests.
Claims Coverage
The independent claims include three inventive features: a pharmaceutical composition, a method for treatment of cancer, and a method of decreasing Valosin Containing Protein-Proteosome pathway activity. Across these claims, the coverage focuses on compounds of Formula IA or Formula IB, and the narrower Formula IA1 or Formula IB1, with specific structural constraints and patient administration conditions.
Pharmaceutical composition with Formula IA or Formula IB fused pyrimidine compounds
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, wherein A is N5 or O; HET is a 5:6 bicyclic aromatic group selected from Formula H5 or Formula H10; R1, R5, R6, R7, and Ar are limited to the specified substituent types and ranges; and Ar is phenyl or fluorophenyl.
Cancer treatment by administering Formula IA1 or IB1 composition with defined structural constraints
A method for treatment of cancer comprising administering to a human patient an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula IA1 or Formula IB1, or a pharmaceutically acceptable salt thereof, wherein A is NH or O; R1 is CO2H or CONH2; R6 is methyl or methoxy; and Ar is phenyl or fluorophenyl.
Decrease of Valosin Containing Protein-Proteosome pathway activity with oral monitored dosing
A method of decreasing Valosin Containing Protein-Proteosome pathway activity in a patient comprising administering to the patient an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula IA1 or Formula IB1, or a pharmaceutically acceptable salt thereof, wherein A is NH or O; R1 is CO2H or CONH2; R6 is methyl or methoxy; Ar is phenyl or fluorophenyl; the pharmaceutical composition is administered orally at a dose of up to 2000 mg of the compound per day; the patient's serum concentration of the compound is monitored to adjust the dosage or timing of administration or both; and the patient has a cancer selected from colorectal cancer, non-small cell lung cancer, multiple myeloma, skin cancer, breast cancer, liver cancer, kidney cancer, head and neck cancer and leukemia.
The claim coverage centers on pharmaceutical compositions defined by Formula IA/IB structural variables and therapeutic methods using narrowed Formula IA1/IB1 constraints. The method claims further specify cancer treatment and decreasing Valosin Containing Protein-Proteosome pathway activity with oral administration, dosing up to 2000 mg per day, and serum concentration monitoring to adjust dosage or timing.
Stated Advantages
p97 inhibitory activity is reported (IC50).
Consistency with oral bioavailability is reported.
Decreasing Valosin Containing Protein-Proteosome pathway activity.
Inhibition of p97 via binding to the p97 active site.
Therapeutic or prophylactic treatment of cancers.
Documented Applications
Use of the fused pyrimidines as p97 proteasome pathway inhibitors, characterized by in vitro ATPase biochemical assay results, cell-based reporter assays using TCRα-GFP, and cultured cancer viability or tumor-like assays.
Treatment of cancer in a human patient selected from colorectal cancer, non-small cell lung cancer, multiple myeloma, skin cancer, breast cancer, liver cancer, kidney cancer, head and neck cancer, and leukemia.
Decreasing Valosin Containing Protein-Proteosome pathway activity in a patient by oral administration with dose limitation and serum concentration monitoring, in the setting of the listed cancers.
Diagnostics/assay concept for measuring p97 inhibition using ubiquitin/ubiquitin-like tagged protein substrates and detectable tag readouts.
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