Vanadyl complexes of hydroxamate chelators and pharmaceutical co

Details Vanadyl complexes of hydroxamate chelators and pharmaceutical co Vanadyl complexes of hydroxamate chelators and pharmaceutical co

1993-06-07

1994-08-16

Dees, Jose G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heavy metal containing doai

514866, 556 42, A61K 3128, C07F 900

Patent

active

053387597

DESCRIPTION:

BRIEF SUMMARY
FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to vanadyl complexes useful for the treatment of diabetes.
Insulin-dependent diabetes mellitus is mainly treated with insulin. Since oral administration of insulin in mammals is ineffective, diabetic patients need to receive insulin by subcutaneous injection. The availability of orally active insulin substitutes is of great importance in the treatment of diabetes.
Vanadate ions (VO.sub.3 -, oxidation state +5) and also vanadyl ions (VO.sup.2+, oxidation state +4) were shown to mimic nearly all of the various actions attributed to insulin in a large variety of in vitro (cellular) systems (Shechter, Y. (1990) Diabetes 39, 1-5) and thus, may be considered as wide-range insulin-mimicking agents. When administered orally (in drinking water) to streptozotocin-treated hyperglycemic rats, vanadate ions reduced the high levels of circulating glucose down to normal values and ameliorated many of the aberrations induced by hyperglycemia, including cardiac performance (Heyliger, C. E. et al (1985) Science 227, 1474-1476). In addition, disorders not directly related to hyperglycemia were also partially cured by oral vanadate therapy in this diabetic experimental model (Rossetti, L. and Laughlin, M. R. (1989) J. Clin. Invest. 84, 892-899). Vanadate therapy is also effective in experimental models of non-insulin dependent diabetes mellitus (NIDDM). In db/db and ob/ob mice, oral vanadate therapy induces long and persistent states of normoglycemia, while subcutaneous injections of insulin fail to do so (Meyerovitch, J. et al. (1991 ) J. Clin. Invest. 87, 1286-1294).
Japanese Patent Application published under No. 2292217 describes vanadium complexes, such as vanadium tartrate, for curing diabetes. U.S. Pat. No. 4,882,171 describes insulin mimic compositions containing a vanadate salt and a peroxide to treat diabetes mellitus. European Patent Application EP 305264 describes vanadyl complexes of cysteine and cysteine derivatives and compositions comprising them for oral treatment of insulin-dependent diabetes. McNeill, J. H. et al (J. Med. Chem. (1992) 35:1489-1491) have described a vanadyl complex of maltol (3-hydroxy-2-methyl-4-pyrone) shown to mimic insulin and to reduce plasma glucose values in rats.
Vanadium salts are thus seriously considered for therapy of human diabetes. Although vanadate has been found to be up to 4-5 fold more effective in vitro than vanadyl in mimicking insulin, probably due to its improved permeability across biological membranes, it has the disadvantage of being 6-10 times more toxic than vanadyl Waters, M. D. (1977) Adv. Med. Toxicol. 2, 147-189; Ramanadham S. et al. (1989) Metabolism 38, 1022-1028). Vanadyl, however, shows low cell permeability. Identifying means to enhance permeability of the less toxic vanadyl at low vanadyl concentrations would therefore open new possibilities for vanadium-based treatment of diabetes.


SUMMARY OF THE INVENTION

The present invention provides novel vanadyl ion (VO.sup.2+) complexes of a chelating compound of general formula I: CO].sub.n NOHR.sup.1 }.sub.2 (I) R.sup.3 independently designate each hydrogen, aryl, aralkyl, or alkyl optionally substituted by X, wherein X is OH, OR.sup.4, OCOR.sup.4, SH, SR, SCOR, COOH, COOR.sup.4, CONH.sub.2, CONHR.sup.4, CONR.sup.4 R.sup.5, NH.sub.2, NHR.sup.4, NR.sup.4 R.sup.5 or NHCOR.sup.4, where R.sup.4 and R.sup.5 are alkyl, and one of R.sup.2 or R.sup.3 may further designate X.
Some of the compounds of formula (I) are the subject of the U.S. Pat. No. 5,101,066 where they are described as tetradentate ligands suitable for the selective extraction of metal ions, such as Cu.sup.2+ or Zn.sup.2 +, from a solution containing a plurality of cations.
It has now been found according to the present invention that the ion carriers of formula I effectively bind and transport vanadyl ions across lipid membranes and potentiate glucose metabolism. The structure of these carriers relies on a dipodal topology which allows a modular assembly of the binders, which in turn

REFERENCES:
patent: 4882171 (1989-11-01), Posner et al.
patent: 5023358 (1991-06-01), Clapiers et al.
patent: 5101066 (1992-03-01), Shanzer et al.
Y. Tor et al.; "Biomimetic Ferric Ion Carriers, Chiral Ferrichrome Analogues"; pp. 6518-6219; Journal of the American Chemical Society, vol. 109, (1987).

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