Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-03-08
2000-02-22
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514258, 544260, 544259, A61K 31505, C07D47508
Patent
active
060280719
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This application relates to a purified composition of the compound 10-propargyl-10-deazaaminopterin and to methods of using this compound in the treatment of tumors.
10-Propargyl-10-deazaaminopterin ("10-propargyl-10dAM") is a member of a large class of compounds which have been tested and in some cases found useful in the treatment of tumors. This compound, which has the structure shown in FIG. 1, was disclosed by DeGraw et al., "Synthesis and Antitumor Activity of 10-Propargyl-10-deazaaminopterin," J. Medical Chem. 36: 2228-2231 (1993) and shown to act as an inhibitor of growth in the murine L1210 cell line and to a lesser extent of the enzyme dihydrofolate reductase ("DHFR"). In addition, some results were presented for the antitumor properties of the compound using the E0771 murine mammary tumor model. This data was equivocal because of the small number of mice used in the test (3 per dosage), the absence of any standard deviation information which would quantify the reliability of the data, and the fact that the highest dose used was in fact toxic to the mice. Nevertheless, assuming this data has some predictive value for the efficacy of a drug in treating human tumors, it would at best predict a drug which, at equivalent levels of tolerance, had properties comparable to or perhaps slightly better than methotrexate.
SUMMARY OF THE INVENTION
Surprisingly, however, more highly purified 10-propargyl-10dAM compositions when tested in a xenograft model for their efficacy against human tumors have now been shown to be far superior to methotrexate ("MTX") and are even superior to edatrexate ("ETX"), a more recent clinical candidate. Moreover, 10-propargyl-10dAM showed a surprising ability to cure tumors such that there was no evidence of tumor growth several weeks after the cessation of therapy. Thus, a first aspect of the present invention is a highly purified composition containing 10-propargyl-10dAM. This composition can be used in accordance with the invention to treat tumors, particularly human mammary tumors and human lung cancer.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the structure of 10-propargyl-10dAM;
FIG. 2 shows an HPLC of an impure 10-propargyl-10dAM preparation prepared in accordance with the prior art;
FIG. 3 shows an HPLC of a highly purified 10-propargyl-10dAM preparation in accordance with the invention;
FIG. 4 shows a synthetic scheme useful in preparing the compound in accordance with the invention;
FIG. 5 summarizes the results of toxicity testing in mice;
FIG. 6 summarizes the results of toxicity testing in rats; and
FIG. 7 shows average plasma concentrations after administration of 10-propargyl-10dAM in dogs.
DETAILED DESCRIPTION OF THE INVENTION
This application relates to "highly purified" 10-propargyl-10dAM. As used in the specification and claims hereof, compositions which are "highly purified" contain 10-propargyl-10dAM substantially free of other folic acid derivatives particularly 10-deazaaminopterin, which can interfere with the antitumor activity of the 10-propargyl-10dAM. A composition within the scope of the invention may include carriers or excipients for formulating the 10-propargyl-10dAM into a suitable dosage unit form for therapeutic use.
10-propargyl-10dAM can be synthesized using the method disclosed in the DeGraw paper, supra or in Example 7 of U.S. Pat. No. 5,354,751 which is incorporated herein by reference. HPLC evaluation of the product prepared by this method shows the presence of a substantial amount (.about.4.6%) of an impurity A (FIG. 2) which has a retention time consistent with 10-deazaaminopterin. Thus, if this synthetic approach is employed further purification is necessary beyond that disclosed in the DeGraw et al. paper. Such purification can be carried out by additional HPLC or crystallization to remove the 10-deazaaminopterin and other folic acid derivatives which may be present.
FIG. 3 shows an HPLC of a highly purified preparation consisting essentially of 10-propargyl-10dAM in accordance with the invent
REFERENCES:
patent: 5354751 (1994-10-01), DeGraw et al.
Starling et al., Cancer Chemotherapy Report Part 1, vol. 58., No. 5., Sep./Oct. 1974.
J.I. DeGraw, W.T. Colwell, J.R. Piper, F.M. Sirotnak, "Synthesis and Antitumor Activity of 10-Propargyl-10-deazaaminopterin" J. Med. Chem., 1993, vol. 36, pp. 2228-2231.
Colwell William T.
DeGraw Joseph I.
Piper James R.
Sirotnak Francis M.
Shah Mukund J.
Sloan-Kettering Institute for Cancer Research
Southern Research Institute
SRI - International
Sripada Pavanaram K.
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