N-oxides and derivatives of chlorambucil for treating hypoxic tu

Details N-oxides and derivatives of chlorambucil for treating hypoxic tu N-oxides and derivatives of chlorambucil for treating hypoxic tu

1994-10-20

1997-02-11

Geist, Gary

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

564 13, C07C22928, C07F 9547

Patent

active

056022786

ABSTRACT:
This invention relates to compounds which are N-oxides and derivatives of chlorambucil and which, under certain conditions, (1) are stable in hypoxic and oxic cells, (2) are toxic in cells having varying degrees of hypoxia, and (3) show little toxicity to oxic cells. These compounds have the general formula set out below and are used to treat tumorous cells: ##STR1## wherein R is an alkyl, aryl, or derivatives thereof, such as CH.sub.3 OCH.sub.2 CH.sub.2 --; CH.sub.3 CH.sub.2 OCH.sub.2 CH.sub.2 --; C.sub.6 H.sub.5 OCH.sub.2 CH.sub.2 --; C.sub.6 H.sub.5 CH.sub.2 --; CH.sub.3 (CH.sub.2).sub.3 OCH.sub.2 CH.sub.2 Cl; or any one of the following: ##STR2##

REFERENCES:
International Conference on Bioreductive Drug Activation Aug. 16-19, 1994--Denny et al.
Mann, et al.--J. Chem. Soc. Perkin Trans. 1 (1991) pp. 2961-2964.
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Denny, W. A. et al.; Chlorambucil N-oxide: A Reappraisal of its Synthesis, Stability, and Selective Toxicity for Hypoxic Cells; International Conference on Bioreductive Drug Activation, Lake Tahoe, California, USA (1994).
Kirkpatrick, D. L. et al.; Synthesis and Bioreductive Potential of a Mono N-oxide Derivative of the Alkylating Agent Chlorambucil; Anti-Cancer Drugs 5:467-472 (1994).
Kirkpatrick, D. L. et al.; Selective Conditions for Bioreductive Activation of the Prodrug, Chlorambucil N-oxide; Proc. AACR 35:3778 (1994).
Mann, J. et al.; Synthesis of Novel N- and S-Mustards as Potential Pro-drugs Activated by Bioreductive Processes; J. Chem. Soc. Perkin Trans. 1:2961-2964 (1991).

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