This invention relates to 1,4-bis-(substituted aminoalkylamino)-anthraquinones, and more particularly to the same as anti-neoplastic agents against animal neoplasms. 1,4-bis-substituted anthraquinones have long been known in the prior art as dyes. For example, U.S. Pat. No. 2,050,661 teaches a process for preparing 1,4-diaminoanthraquinone which is suitable for use for dying cellulose esters and ethers or for coloring fats, oils, waxes, and the like. U.S. Pat. No. 1,199,176 teaches the use of 1,4-bis-(alpha, beta-diphenolethylamino) anthraquinone and the like for dying wool and other animal fibers.
A method for the production of 1,4-bis-(substitued aminoalkylamino)-anthraquinones is also known in the art ("The reaction of leucoquinizarines with alkylenediamines", Greenhalgh and Hughs, J. Chem. Society (C), page 1284 (1968)).
Certain naturally occurring substituted anthraquinones, namely, 2,6-bis-substituted and 2,7-bis-substituted anthraquinones, have been found to give indications of possible anti-neoplastic inhibitory effects. Generally, these have been reported as inhibitions of DNA polymerases by intercalation between base pairs of DNA double helix. The intercalation theory has been used as a working hypothesis to explain the activity of many anti-cancer drugs including actinomycin D, daunorubicin, adriamycin, anthramycin, and coralyne. However, certain of these drugs, even though recognized as very promising and definitely showing good inhibitory activity against leukemia as well as solid tumors, have the disadvantage that they or their metabolites cause severe and irreversible cardio toxicity which could be fatal if the accumulated dose of these drugs exceeds a limited amount. Additionally, they are all naturally produced.
Certain in vivo testing systems and protocols have been developed by the National Cancer Institute for testing compounds to determine their suitability as antineoplastic agents. These have been reported in Cancer Chemotherapy Reports, Part III, Vol. 3, No. 2, (1972), Deran, Greenberg, MacDonald, Schumacher and Abbott. These protocols have established standardized screening test which are generally followed in the field of testing for antineoplastic agents. Three of these systems are particularly significant to the present invention. These are lymphoid leukemia L1210, lymphocytic leukemia P388 and melanotic melanoma B16. All of these neoplasms are found in mice. Initial screening is usually done with P388 leukemia and B16 melanoma if the initial tests appear promising. Generally, good antineoplastic activity shown in these protocols by a percentage increase of mean survival times of the test animals over the control animals is predictive of similar results in human leukemias. A mean survival time ratio of test over control (with the control group representing 100%) of 125% is considered necessary to demonstrate antineoplastic activity by the substance being tested. Further detailed description of these protocols is presented hereinbelow in the detailed description of the invention.