Tricyclic 1,2,4-Triazine Oxides and Compositions for Therapeutic Use in Cancer Treatments
申请人:Hay Michael Patrick
公开号:US20090186886A1
公开(公告)日:2009-07-23
The invention relates to novel tricyclic 1,2,4-triazine-1-oxides and novel tricyclic 1,2,4-triazine-1,4-dioxides of formula I
and to related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.
Tricyclic [1,2,4]Triazine 1,4-Dioxides As Hypoxia Selective Cytotoxins
作者:Michael P. Hay、Kevin O. Hicks、Karin Pchalek、Ho H. Lee、Adrian Blaser、Frederik B. Pruijn、Robert F. Anderson、Sujata S. Shinde、William R. Wilson、William A. Denny
DOI:10.1021/jm800967h
日期:2008.11.13
A series of novel tricyclic triazine-di-N-oxides (TTOs) related to tirapazamine have been designed and prepared. A wide range of structural arrangements with cycloalkyl, oxygen-, and nitrogen-containing Saturated rings fused to the triazine core, coupled with various side chains linked to either hemisphere, resulted in TTO analogues that displayed hypoxia-selective cytotoxicity in vitro. Optimal rates of hypoxic metabolism and tissue diffusion coefficients were achieved with fused cycloalkyl rings in combination with both the 3-aminoalkyl or 3-alkyl substituents linked to weakly basic soluble amines. The selection was further refined 7 using pharmacokinetic/phamacodynamic model predictions of the in vivo hypoxic potency (AUC(req)) and selectivity (HCD) with 12 TTO analogues predicted to be active in Vivo, Subject to the achievement of adequate plasma pharmacokinetics.
TRICYCLIC 1,2,4-TRIAZINE OXIDES AND COMPOSITIONS THEREFROM FOR THERAPEUTIC USE IN CANCER TREATMENTS
申请人:AUCKLAND UNISERVICES LIMITED
公开号:EP1866292B1
公开(公告)日:2010-12-15
US7989451B2
申请人:——
公开号:US7989451B2
公开(公告)日:2011-08-02
[EN] TRICYCLIC 1,2,4-TRIAZINE OXIDES AND COMPOSITIONS THEREFROM FOR THERAPEUTIC USE IN CANCER TREATMENTS<br/>[FR] OXYDES DE 1,2,4-TRIAZINE TRICYCLIQUES ET LEURS COMPOSITIONS A USAGE THERAPEUTIQUE DANS LES TRAITEMENTS ANTICANCEREUX
申请人:AUCKLAND UNISERVICES LTD
公开号:WO2006104406A1
公开(公告)日:2006-10-05
[EN] The invention relates to novel tricyclic 1,2,4-triazine-1-oxides and novel tricyclic 1,2,4-triazine-1,4-dioxides of formula: (I); and to related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs. [FR] La présente invention se rapporte à des 1-oxydes de 1,2,4-triazine tricycliques innovants et à des 1,4-dioxydes de 1,2,4-triazine tricycliques innovants de formule : (I), ainsi qu'aux analogues apparentés. Elle se rapporte également à leur préparation et à leur utilisation en tant que médicaments sélectifs de l'hypoxie et que radiosensibilisants destinés au traitement du cancer, seuls ou en combinaison avec une radiothérapie et/ou d'autres médicaments anticancéreux.