Imidazotetrazine compounds

A compound and alkyl technology, applied in the field of imidazolium tetrazine compounds, can solve the problems of unclear maximum curative effect and other issues

Pending Publication Date: 2021-08-17
THE BOARD OF TRUSTEES OF THE UNIV OF ILLINOIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Specifically, it is unclear whether 2 hours is optimal for maximum efficacy, perhaps a shorter (or longer) half-life would be more effective

Method used

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  • Imidazotetrazine compounds

Examples

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preparation example Construction

[0155] The invention also relates to processes for the preparation of said compounds and compositions. The compounds and compositions can be prepared by any suitable technique of organic synthesis, such as those described herein. Many such techniques are known in the art. Many such known techniques are described in the following documents: Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol.3,Louis S.Hegedus and Leroy Wade,1977;Vol.4,Leroy G.Wade,Jr.,1980;Vol.5,Leroy G.Wade,Jr.,1984;and Vol.6,Michael B. Smith; and standard organic reference books such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th Ed.by M.B.Smith and J.March (John Wiley&Sons, New York, 2001), Comprehensive Organic Synthesis; Selectivity, Strategy & Efficiency in Modern Organic Chemistry, in 9Volumes, Barry M.Trost, Ed.-in-Chief (Pergamon Press, New ...

Embodiment 1

[0186] Example 1: Experimental information on biological data

[0187] Cell Culture and Reagents: All cell lines were maintained at 37°C, 5% CO 2 and a humid environment in a medium containing 1% penicillin / streptomycin. Cell culture conditions were as follows: Traditional cell lines U87 and T98G were grown in EMEM with 10% FBS. Traditional cell lines D54 and U118MG were grown in DMEM with 10% FBS. HGCC patient-derived cell line U3054MG 1 Cultured under serum-free stem cell conditions (1:1 Neurobasal:DMEM / F12 medium supplemented with B27, N2, hEGF and hFGF). GBM hookococcus cell line Br23c 2 Cultures were performed with NeuroCult NS-A proliferation kit (Stem Cell Technologies) supplemented with 0.0002% heparin, hEGF and hFGF. Temozolomide (TMZ) was purchased from AK Scientific. TMZ analogs were synthesized as described below. Compounds were dissolved in DMSO (1% final concentration, Fisher Chemical) for cell culture studies.

[0188] Cell Viability Assay: Cells were ha...

Embodiment 2

[0194] Embodiment 2: synthetic method

[0195] Materials and methods: Chemical reagents were purchased from commercial sources and used without further purification. Flash chromatography uses silica gel (230-400 mesh). The anhydrous solvent was dried by passing it through a column packed with activated alumina under a positive pressure of nitrogen. All reactions were performed in oven-dried glassware under a nitrogen atmosphere with magnetic stirring unless otherwise stated. 1 H and 13 C NMR spectra were recorded on a Bruker 500 (500MHz, 1 H; 125MHz, 13 C) or Varian Unity Inova 500 (500MHz, 1 H) MHz spectrometer. Spectra were referenced using residual chloroform (δ = 7.26ppm, 1 H; 77.16ppm, 13 C) or dimethyl sulfoxide (δ=2.50ppm, 1 H; 39.52ppm, 13 C). Multiplicity is expressed as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad). The coupling constant J is expressed in Hertz (Hz). High resolution mass spectrometry (HRMS) was performe...

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Abstract

New synthetic methods to provide access to previously unexplored functionality at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.

Description

[0001] related application [0002] This application claims priority under U.S.C. §119(e) to the following earlier applications: U.S. Provisional Patent Applications 62 / 716,390 filed August 9, 2018, 62 / 778,750 filed December 12, 2018, and 2019 62 / 873,669 filed July 12. The aforementioned prior application is hereby incorporated by reference. [0003] governmental support [0004] This invention was made with Government support under grant R21-CA195149 through the National Institutes of Health, USA. The US Government has certain rights in this invention. Background technique [0005] Glioblastoma multiforme (GBM) is the most prevalent, aggressive and lethal primary malignant brain tumor, with only 10% of patients surviving five years 1 . The current standard of care for GBM is major surgical resection followed by radiation therapy with temozolomide (TMZ), a small molecule DNA alkylating agent. The antitumor effect of TMZ is ultimately through the O of the guanine residue ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/41A61K31/4164A61K31/4188C07D235/02C07D487/04
CPCC07D487/04A61K9/2009A61K9/2013A61K9/2018A61K9/2027A61K9/2054A61K9/2059A61K9/485A61K9/4858A61K9/4866A61K47/02A61K47/24A61K47/26A61K47/34A61K47/36A61K31/495A61P35/00
Inventor 保罗·J·赫根罗德蒂莫西·M·范瑞利·L·斯维克
Owner THE BOARD OF TRUSTEES OF THE UNIV OF ILLINOIS
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