Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1994-04-19
1998-03-17
Wilson, James O.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 45, 514 49, 514256, 514257, 514261, 514274, 514300, 435 25, 536 2713, 536 2714, 536 2721, 536 276, 536 281, 536 282, 536 285, 536 2853, 544242, 544245, 544264, 544317, A01N 4304
Patent
active
057286841
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to prodrugs metabolizable by the liver, and more particularly relates to treating disease using a prodrug metabolizable by a liver enzyme(s) to an active drug. It also concerns a method of ascertaining if a prodrug is useful for treating a disease.
BACKGROUND OF THE INVENTION
Iododeoxyuridine (IUdR) was synthesized as an anti-neoplastic agent in 1959 by Prusoff (Prusoff, W. H., (1959), Biochem. Biophys. Acta, 32, 295-296), and was the first thymidine analog clinically used as an anti-herpes agent (Kaufman, H. E., Martola, E. L. and Dohlman, C., (1962), Archs. Ophthalmol., 68, 235-239). The toxicities associated with IUdR when used systemically limited its clinical usage. IUdR was also recognized as a potential clinical radiosensitizer for cancer chemotherapy (Kinsella, T. J., Mitchell, J. B., Russo, A., Morstyn, G. and Glatstein, E., (1984), J. Radiation Oncology Biol. Phys., 10, 1399-1406). The degree of radiosensitization is directly dependent on the amount of thymidine replacement in DNA by this analog (Speth, P. A. J., Kinsella, T. J. Chang, A. E. Klecker, R. W., Belanger, K. and Collins, J. M., (1988), Clin. Pharmacol. Ther. 44, 369-375). Intrahepatic infusion of IUdR followed by radiation for the treatment of tumor cells in liver has had some success (Remick, S. C., Benson III, A. B., Weese, J. L., Willson, J. K. V., Tutsch, K. D., Fischer, P. H. and Trump, D. L., (1989), Cancer Res. 49 6437-6442).
In an attempt to develop selective anti-herpes simplex virus (HSV) agents based on the broader spectrum of substrate specificity of thymidine kinase of the herpes simplex virus compared to the human thymidine kinase, 5-iodo-2-pyrimidinone-deoxyribose (IPdR)--which differs from IUdR by a double bonded oxygen at the 4-position of the base--was synthesized. IPdR was found to have potent activity against HSV-1 and HSV-2 in cell culture and against HSV-2 in mice (Lewandowski, G. A., Grill, S. P., Fisher, M. H., Dutschman, G. E., Efange, S. M., Bardos, T. J. and Cheng, Y. C., (1989), Antimicrob. Agents Chemother., 33, 340-344). This agent was not toxic to uninfected cells, nor to mice when given orally at the dosage employed (Lewandowski, G. A., Grill, S. P., Fisher, M. H., Dutschman, G. E., Efange, S. M., Bardos, T. J. and Cheng, Y. C., (1989), Antimicrob. Agents Chemother., 33, 340-344). Since IPdR and IUdR are structurally related, the possible conversion of IPdR to IUdR was examined. It was shown previously that IPdR could not be converted to IUdR by xanthine oxidase (Lewandowski, G. A., Grill, S. P., Fisher, M. H., Dutschman, G. E., Efange, S. M., Bardos, T. J. and Cheng, Y. C., (1989), Antimicrob. Agents Chemother., 33, 340-344)
U.S. Pat. Nos. 4,895,937 discloses the nucleoside 1-(2-deoxy-.beta.-D-ribofuranosyl)-5-(iodo)-2-pyrimidinone (IPdR) for use as an agent against herpes viruses, for example HSV-2. The entire content of U.S. Pat. No. 4,895,937 is incorporated by reference herein.
NOMENCLATURE
SUMMARY OF THE INVENTION
It is an object of the present invention to provide compositions for use as prodrugs which are metabolizable in the mammalian liver into a biologically active substance, particularly a biologically active substance which is intended to exert its biological effect in the liver or one which cannot be administered orally.
It is another object of the present invention to provide compositions comprising 5-substituted PdR analogs, particularly IPdR, for use as prodrugs which are metabolizable in the mammalian liver (especially the human liver) to form in situ the corresponding biologically active 5-substituted UdR compounds.
It is a further object of the present invention to use such 5-substituted PdR analogs for treatment of liver-associated diseases and particularly as a radiosensitizer for hepato-carcinoma.
It is still a further object of the present invention to provide compositions other than 5-substituted PdR analogs for use as prodrugs which are metabolizable in the mammalian liver into a biologically active substance, parti
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Chang Chien-Neng
Cheng Yung-Chi
Wilson James O.
Yale University
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