Derivatives of swainsonine and their use as therapeutic agents

#The present invention relates generally to novel derivatives of swainsonine, processes for their preparation and their use as therapeutic agents.

#Swainsonine (SW) is an indolizidine alkaloid found in Australian Swainsona canescens (Colegate et al., Aust J Chem 32:2257-2264, 1979), North American plants of the genera Astragalus and Oxytropis (Molyneux R J and James L F., Science 215:190-191, 1981), and also the fungus Rhizoctonia leguminicola (Schneider et al., Tetrahedron 39;29-31, 1983). The alkaloid is a potent inhibitor of the Golgi enzyme .alpha.-mannosidase II, an enzyme required for maturation of N-linked oligosaccharides on newly synthesized glycoproteins. SW also blocks lysosomal .alpha.-mannosidases causing the accumulation of oligomannose chains in cells exposed to the drug (Tulsiani et al., J. Biol. Chem. 257:7936-7939, 1982).

#The SW block in Golgi processing prevents expression of the .beta.16GlcNAc branched "complex-type" N-linked oligosaccharides which has been observed to increase following malignant transformation in human and rodent cells (Fernandes et al., Cancer Res. 51:718-723, 1991 and Dennis, J. W., pp. 161-194. CRC Press, Boca Raton, 1991). The branched oligosaccharides appear to play a role in cancer metastasis, as loss or truncation of the structures due to somatic mutations in metastatic tumor cell lines results in greatly reduced metastasis and slower solid tumor growth (Dennis et al., Science 236:582-585, 1987 and VanderElst I. and Dennis J. W., Exp. Cell Res. 192:612-613, 1991). Furthermore, SW-treated murine tumor cells are less metastatic in both organ-colonization and spontaneous metastasis assays in mice (Dennis J. W., Cancer Res. 46:5131-5136, 1986 and Humphries et al., Proc. Natl. Acad. Sci. USA 83:1752-1756, 1986).

#The invention will be better understood with reference to the drawings in which:

#FIGURE 1 is a schematic diagram of a novel reaction for preparing swainsonine.

#As hereinbefore mentioned the present invention relates to a compound of the formula I ##STR5## wherein one or two of R.sup.1, R.sup.2, and R.sup.3 are the same or different and represent hydroxyl, halo, amino, or alkoxy, and the others of R.sup.1, R.sup.2, and R.sup.3 represent hydroxyl or hydrogen, and one of R.sup.4, R.sup.5, and R.sup.6 represents alkyl, or aryl, and the other of R.sup.4, R.sup.5, and R.sup.6 represents hydrogen.

#As used herein the term "alkyl" refers to a straight or branched chain hydrocarbon radical containing no unsaturation and having 1 to 4 carbon atoms. Examples of alkyl groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, methylcyclopropyl, methylcyclohexyl, and cyclobutyl. The term "aryl" used herein refers to radicals having the ring structure characteristic of benzene. Examples of aryl groups are benzyl, pNO-benzyl, and p-methoxybenzyl. The term "alkoxy" refers to a substituent which consists of an alkyl or aryl linked through an ether oxygen having its free valence bond from the ether oxygen. Examples of alkoxy groups are O-methyl, O-allyl, O-propyl, O-benzyl, O-pNO-benzyl and O-p-methyl-benzyl. The term "halogen" refers to a member of the family fluorine, chlorine, bromine, or iodine.

#In one embodiment of the invention, compounds of the formula I are provided where R.sup.6 is alkyl or aryl, R.sup.1 and R.sup.2 are hydroxyl, halo, amino or alkoxy, R.sup.3 is hydrogen, hydroxyl, alkoxy, halo, and amino, and R.sup.4 and R.sup.5 are hydrogen. In another embodiment, compounds of the formula I are provided wherein R.sup.5 is alkyl or aryl, R.sup.1 and R.sup.2 are hydroxyl, alkoxy, halo or amino, R.sup.3 is hydrogen, hydroxyl, alkoxy, halo, and amino, and R.sup.4 and R.sup.6 are hydrogen. In yet a further embodiment, compounds of the formula I are provided where R.sup.4 is alkyl or aryl, R.sup.1 and R.sup.2 are hydroxyl, alkoxy, halo or amino; R.sup.3 is hydrogen, hydroxyl, alkoxy, halo or amino, and R.sup.5 and R.sup.6 are hydrogen.