Auckland Uniservices Limited

Cancer Research Technology Limited

Cancer Research Campaign Technology Limited

Warner-lambert Company

Mewburn Ellis

William Robert Wilson

William Alexander Denny

Bronwyn Gae Siim

Graham John Atwell

Adam Vorn Patterson

Brian Desmond Palmer

Michael Patrick Hay

Shangjin Yang

Moana Tercel

Ho Huat Lee

Jeffrey Bruce Smaill

Amir Ashoorzadeh

Guo-Liang Lu

David C Ware

Kevin Owen Hicks

Karin Pchalek

Frederik Bastiaan Pruijn

Ralph James Stevenson

Robert Forbes Anderson

Alexandra Marie Mowday

Adrian Blaser

Stephen Michael Frazer Jamieson

Kendall Marie Carlin

Andrej Maroz

Huai-Ling Annie Hsu

Nuala Ann Helsby

Jared Bruce Milbank

Frederik Bastlaan Pruijn

Moena Tercel

The invention provides kinase inhibitors of Formula I:  Also provided are reductive prodrugs, comprising a kinase inhibitor as defined above and a reductive trigger linked directly or indirectly to a nitrogen of the kinase inhibitor. Further provided are pharmaceutical compositions, comprising the kinase inhibitors or the prodrugs, and the use of such compositions in therapy, in particular for treating cancer.

Kinase inhibitors, prodrug forms thereof and their use in therapy

The invention provides novel prodrug compounds comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, where the compound carries a positive charge. In preferred embodiments, the compounds are of Formula I: where: X is any negatively charged counterion; Ris a group of the formula &#x2014;(CH)Tr, where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and &#x2014;(CH)Tr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6; R, Rand Rmay each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R)(R)(R)N, or two of R, R, and Rmay form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R, Rand Rmay be absent and two of R, Rand Rform an aromatic heterocyclic amine ring of a kinase inhibitor. The compounds of the invention are useful in treating proliferative diseases such as cancer.

Prodrug forms of kinase inhibitors and their use in therapy

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 oxides and compositions for therapeutic use in cancer treatments

The present invention relates to synergistic combinations of the compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and vinca alkaloids, which have anti-tumour activity. Preferably, the present invention relates to synergistic combinations of the compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and vincristine. More particularly, the invention is concerned with the use of such combinations in the treatment of cancer and pharmaceutical compositions containing such combinations. The invention further provides for methods of preparing the combinations of the invention.

Anti-cancer combinations

The present invention relates to synergistic combinations of the compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and an alkylating agent, which has anti-tumour activity. Preferably, the present invention relates to synergistic combinations of the compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and cyclophosphamide. More particularly, the invention is concerned with the use of such combinations in the treatment of cancer and pharmaceutical compositions containing such combinations. The invention further provides for methods of preparing the combinations of the invention.

The present invention relates to synergistic combinations of the compound 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) and a compound selected from anthracyclines and topisomerase II inhibitors, which have anti-tumor activity. Preferably, the present invention relates to synergistic combinations of the compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and a compound selected from etoposide, and doxorubicin. More particularly, the invention is concerned with the use of such combinations in the treatment of cancer and pharmaceutical compositions containing such combinations. The invention further provides for methods of preparing the combinations of the invention.

The present invention relates to synergistic combinations of the compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and a compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors, which have anti-tumour activity. Preferably, the present invention relates to synergistic combinations of the compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and a compound selected from carboplatin, gemcitabine, cisplatin, 5-fluorouracil, cyclophosphamide, etoposide, vincristine, doxorubicin and irinotecan. More particularly, the invention is concerned with the use of such combinations in the treatment of cancer and pharmaceutical compositions containing such combinations. The invention further provides for methods of preparing the combinations of the invention.

The present invention relates to synergistic combinations of the compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and a platinum compound which has anti-tumour activity. Preferably, the present invention relates to synergistic combinations of the compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and carboplatin. More particularly, the invention is concerned with the use of such combinations in the treatment of cancer and pharmaceutical compositions containing such combinations. The invention further provides for methods of preparing the combinations of the invention.

The compound 3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1,4-dioxide and pharmacologically acceptable salts thereof. A method of treating cancer in a subject is also described in which 3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1,4-dioxide or a pharmacologically acceptable salt thereof is administered to tumor cells in a hypoxic environment. Also described is a method of radiosensitising in a subject tumor cells of solid tumors in hypoxic conditions by administering to the subject a pharmaceutical composition containing 3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1,4-dioxide or a pharmacologically acceptable salt thereof in an amount sufficient to produce radiosensitivity in the tumor cells, and subjecting the tumor cells to radiation. A pharmaceutical composition is additionally provided containing a therapeutically effective amount of 3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1,4-dioxide or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser.

1,2,4-benzotriazine-1,4-dioxides

Nitroaniline-based unsymmetrical mustards of the general formula (I) are provided, together with methods of preparation and methods for their use as prodrugs for gene-dependent enzyme prodrug therapy (GDEPT) and cell ablation therapy in conjunction with nitroreductase enzymes as hypoxia selective cytotoxins and as anticancer agents.

Nitroaniline-based alkylating agents and their use as prodrugs

The present invention relates generally to nitro-1,2-dihydro-3H-benzo[e]indoles and 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.

Nitrobenzindoles and their use in cancer therapy

The present invention relates to a novel nitrophenyl mustard and nitrophenylaziridine alcohols, to their corresponding phosphates, to their use as targeted cytotoxic agents; as bioreductive drugs in hypoxic tumors, and to their use in cell ablation, including gene-directed enzyme-prodrug therapy (GPEPT) and antibody-directed enzymeprodrug therapy (ADEPT), in conjunction with nitroreductase enzymes.

Nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents

This invention relates to a class of heterocycles and their metal complexes, and is particularly concerned with the use of these compounds in the preparation of prodrugs or as prodrugs that may be activated under hypoxic conditions by enzymes or by therapeutic ionising radiation, in the treatment of cancer. The invention also relates to the use of these heterocycles and the corresponding metal complexes in the preparation of medicaments and to compositions including the heterocycles or their metal complexes and to methods for preparing these compounds.

Anti-cancer 2,3-dihydro-1H-pyrrolo[3,2-f]quinoline complexes of cobalt and chromium

Combination therapy for cancer

A range of aziridin-1-yl nitrobenzamides are provided for use as prodrugs in conjunction with nitroreductase (NR) enzymes. The amides may have 1 or 2-substituents which may be bulky and polar. For example, 5-(aziridin-1-yl)-N-&lsqb;2-(4-morpholino)ethyl&rsqb;-2,4-dinitrobenzamide of Formula (A) was found to be highly active against all NR&plus; cell lines tested.

Growing community of inventors

Waiuku, New Zealand

William Robert Wilson