The invention relates to addition products between .alpha.-keto-aldehydes and secondary amines
.alpha.-KETO-ALDEHYDES ARE WELL KNOWN AND USUALLY ARE PREPARED THROUGH OXIDATION (Riley, H. L., Morley, J. F., and Friend, N.A.C.: J.Chem.Soc. 1932.1875; Rabjohn, N.: in Organic Reactions 5.331.1949; and Waitkins, G. R., and Clark, C. W.: Chem.Rews 36, p. 235, 1945) of the active methylene groups to carbonyl groups by means of selenous acid (H.sub.2 SeO.sub.3). It has also been known that these .alpha.-keto-aldehydes are potential inhibitors of in vitro and in vivo cell division (Egyud, L. G.: Proc.Natl.Acad.Sci. 54, p. 200, 1965; Egyud, L. G. and Szent-Gyorgyi, A.: Proc.Natl.Acad.Sci. 55, p. 388, 1965; Szent-Gyorgyi, A., Egyud, L. G., and McLaughlin, J.: Sci. 155, p. 359, 1967; Egyud, L. G.: Curr.Mod.Biol. 1, p. 14, 1967; Egyud, L. G., and Szent-Gyorgyi, A.: Proc.Natl.Acad. Sci. 56, p. 203, 1966; Egyud, L. G., and Szent-Gyorgyi, A.: Sci. 160, p. 1140, 1968; Apple, M. A., and Greenberg, D. M.: Can.Chem.Ther.Rep. 51, p. 455, 1967; Kenny, C. P., and Sparkes, B. G.: Sci. 161, p. 1344, 1968; Sparkes, B. G. and Kenny, C. P.: Proc.Natl.Acad.Sci. 64, P. 920, 1969; Gregg, C. T.: Eptl.Cell Res. 50, p. 65, 1968; and Scaife, J. F.: Experientia 25, p. 178, 1969).
The .alpha.-keto-aldehydes are further known as potent anti-viral agents (Baylor, M., and Egyud, L. G.: Virology 31, p. 380, 1967; De Bock, C. A. in Nature 179, p. 706, 1957; Cavallini, C. et al. in J. Medicinal Pharamceut. Chem. 1, p. 365, 1959; Engle, C. C. et al. in J.Immunol. 89 531, 1962; Underwood, C. R. et al. in Proc.Soc.Exptl.Biol.Med.; 93, p. 421, 1956; Tiffany, B. D. et al. in J.Amer.Chem.Soc. 79, 1682, 1957). In recent research the inhibition of cell division with .alpha.-keto-aldehydes has been related to the blocking of protein synthesis (Otsuka, H. and Egyud, L. G.: Can.Res. 27, p. 1498, 1967; and Otsuka, H. and Egyud, L. G.: Curr.Mod.Biol. 2, p. 106, 1968). Cancer cells have been shown to possess an increased sensitivity to .alpha.-keto-aldehydes which may be explained by a specific reaction between the keto-aldehydes and guanine residues present in the excessive amounts of s-RNA-s in the cell (Shapiro, R.: Ann.N.Y.Acad.Sci. 163, art. 2, p. 624, 1969; Shapiro, R. and Hachmann, J.: Biochem. 5, p. 2799, 1966; and Litt, M. and Hancock, F.: Biochem. 6, p. 1848, 1967).
However, these .alpha.-keto-aldehydes exhibit a relatively high toxicity in animals. They are moreover readily metabolized to the corresponding .beta.-hydroxy acids by glyoxalases, the enzyme system that is ever-present in all living cells.
The inhibitory action of the .alpha.-keto-aldehydes on cell division is furthermore reversed upon addition of thiols (Egyud, L. G.: Curr.Mod.Biol. 2, p. 128, 1968).
It is therefore an object of the present invention to modify the .alpha.-keto-aldehydes in a manner such that they are protected against the action of glyoxalases while at the same time their in vivo toxicity is decreased and their tumor specificity is enhanced. The incorporation of a blocking group as indicated in the .alpha.-keto-aldehydes is known as "latentiation". In a general way, the latentiation of the .alpha.-keto-aldehydes is thus the object of the present invention.
USPTO Backgrounds
USPTO Backgrounds