Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-25
2001-07-31
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S188000, C544S004000, C544S064000, C544S181000, C544S225000, C546S006000, C546S007000, C549S003000, C549S210000
Reexamination Certificate
active
06268357
ABSTRACT:
BACKGROUND OF THE INVENTION
Vanadium is a trace metal in biological systems and in the environment. Pure anadium is a soft, bright white metal. Like other transition metals, it forms complexes that are often beautifully colored. Vanadium exists in several oxidation states. The most frequently encountered in biological systems are the oxovanadium(V) ion, e.g. vanadate, sodium orthovanadate and sodium metavanadate; and the oxovanadium(IV) ion, e.g. vanadyl and vanadyl sulfate. Other compounds are known in the −1 to +5 oxidation states.
Vanadium(III) oxide is a black refractory substance made by the reduction of V
2
O
5
with hydrogen or carbon monoxide. V
2
O
3
is entirely basic in nature, and dissolves in acids to give the V(III) aquo ion or its complexes. The blue aquo ion [V(H
2
O)
6
]
3+
can be obtained as above, or by electrolytic or chemical reduction of V(IV) or V(V) solutions. V(III) forms a number of complex ions, mostly anionic, e.g. [V(CN)
6
]
3−
, but some are neutral. Coordination complexes of vanadium(III) have been described, including tris(acetylacetonatovanadium(III) (Morgan et al. (1913)
J. Chem. Soc
. 103:78-90); tris(tropolonato)vanadium(III) (Eaton et al. (1973)
J. Am. Chem. Soc
. 94(4):1116-1124); and the trianionic V(III) complex tripotassium tris(catecholato) vanadate(III) (Cooper et al. (1982)
J. Am. Chem. Soc
. 104(19):5092-5102). Sommer (1962)
Z. Anal. Chem
. 185:263-266 disclose the formation of an intensely purple or blue-violet color formed from vanadium(V) with maltol in a medium of 40% H
3
PO
4
and oxalic, purportedly due to an instable V(III) complex of unknown composition.
Relatively little is known about the biological effect or role of vanadium in the (III) oxidation state. However, sea squirts (ascidians) have a highly unusual requirement for vanadium. The concentration of vanadium in sea squirts is a million times higher than in sea water as a consequence of their ability to concentrate vanadium. Lybing (1953)
Ark. Khem
. 6:261 discloses that vanadium in ascidians is predominantly in the +3 oxidation state, based on a comparison of optical spectra. A more recent evaluation of the changes in vanadium coordination and oxidation state in ascidians may be found in Taylor et al. (1994)
J Inorg Biochem
56(2):97-116.
More recently, complexes of vanadium(III) with cysteine, and the dipeptide N-(2-mercaptoproprionyl)-glycine were tested in a rat benzopyrene-induced tumor model (Evangelou et al. (1997)
Cancer Letters
119(2):221-225). It was found that the [V
III
(Hcys)
3
] complex had a significant antitumor effect.
In the (IV) and (V) oxidation state, vanadium has been found to have a number of interesting properties in biological systems. Vanadium was originally recognized for its ability to inhibit membrane Na
+
-K
+
-ATPase, but various laboratory studies now document that this element has the capacity to affect the activity of various intracellular enzyme systems, and may modify their physiological functions.
For example, complexes of vanadium(IV) with &agr;-hydroxypyrones and &agr;-hydroxypyridinones have been shown to have an effect in a number of studies. Yuen et al. (1997)
J Inorg Biochem
68(2):109-116 compare vanadium complexes bis(kojato)oxovanadium(IV) and bis(maltolato)oxovanadium(IV) for their glucose lowering properties. Work by McNeill et al. (see Am. J. Physiol 257: H904-H911 (1989), Metabolism 38: 1022-1028 (1985), Diabetes 38: 1390-1395 (1989) and Can. J. Physiol & Pharmacol. 68: 486491 (1990); U.S. Pat. Nos. 5,527,790; 5,300,496; has shown that vanadyl administered orally as vanadyl sulfate, or as vanadyl maltol complexes, lowers blood glucose and blood lipids in STZ diabetic rats and prevents secondary complications of diabetes such as cataracts and cardiac dysfunction.
The profound effects of vanadium in biological systems makes their synthesis and evaluation a subject of great interest. Novel compounds of vanadium(III) may be explored for their activity in regulating blood glucose, proliferative diseases, bone growth, and other conditions.
SUMMARY OF THE INVENTION
Stable organic complexes of vanadium in the 3+ oxidation state are provided. The complexes have the general structure VL
3
, where V is vanadium(III) and L is a monoprotic bidentate ligand that forms a five-membered, unsaturated vanadium containing ring, having vanadium coordinating oxygen or sulfur ring heteroatoms, and where the vanadium containing ring is fused to a six-membered heterocyclic ring. Preferably L is a hydroxypyrone or a hydroxypyridinone. Such V(III) complexes may be provided in an isolated form, or in a composition with other agents, e.g. physiologically acceptable carriers. The complexes may also be provided as a hydrate, e.g. VL
3
•(H
2
O)
n
, or as a salt or adduct, e.g. VL
3
•(Z)
m
where Z may be HCl, ascorbic acid, bicarbonate, etc. The complexes have a number of uses, including the treatment of elevated blood glucose and related disorders, treatment of proliferative disorders, etc.
REFERENCES:
patent: 5278154 (1994-01-01), Lacoste
patent: 5300496 (1994-04-01), McNeill et al.
patent: 5527790 (1996-06-01), McNeill et al.
patent: 98/49173 (1998-11-01), None
Cooper, Stephen R., et al., “Synthetic, Structural, and Physical Studies of Bis(triethylammonium) Tris(catecholato)vanadate(IV), Potassium Bis(catecholato)oxovanadate(IV), and Potassium Tris(catecholato)vanadate(III),”J. Am. Chem. Soc.(1982) vol. 104:5092-5102.
Eaton, S.S., et al., “Intramolecular Rearrangement Reactions of Tris-Chelate Complexes. IV.1Further Investigation of the Rearrangements of Tris(&agr;-isopropenyl-and &agr;-isopropyltropolonato)metal(III,IV) Complexes,”J. Amer. Chem. Soc.(1973) vol. 95(4):1116-1124.
Evangelou, Angelos, et al., “Comparison of the Therapeutic Effects of Two Vanadium Complexes Administered at Low Doses on Benzo [&agr;] Pyrene-Induced Malignant Tumors in Rats,”Cancer Letters(1997) vol. 119:221-225.
Lybing, Sigvar, “The Valence of Vanadium in Hemolysates of Bloodcells fromAscidia ObliquaAlder,”ARKI&ngr; FÖR KEMIBand 6 nr 21 Communicated Feb. 11, 1953 by John Runnstrom; pp.: 261-269.
Pederson, Raymond A., et al., “Long-Term Effects of Vanadyl Treatment on Streptozocin-Induced Diabetes in Rats,”Diabetes(Nov. 1989) vol. 38:1390-1395.
Ramanadham, S., et al., “Enhanced In Vivo Sensitivity of Vanadyl-Treated Diabetic Rats to Insulin,”J. Physiol. Pharmacol.(1990) vol. 68:486-491.
Ramanadham, Sasanka, et al., “Oral Vanadyl Sulfate in Treatment of Diabetes Mellitus in Rats,”Am . J. Physiol.(1989) (Heart Circ. Physiol. 26):H904-H911.
Ramanadham, Sasanka, et al., “Sustained Prevention of Myocardial and Metabolic Abnormalities in Diabetic Rats Following Withdrawl from Oral Vanadyl Treatment,”Metabolism(Oct. 1989) vol. 38(10):1022-1028.
Sommer, L. Von, “Ein Selektiver von Vanadium mit Maltol,”Aus dem Institut für analytiscle der J.E. Purkyn{haeck over (e)}-Universität, Brno(CSSR), (Sep. 1961) pp.: 263-266.
Taylor, Steven W. et al., “Vanadium in Ascidians: Changes in Vanadium Coordination and Oxidation State Upon Cell Lysis,”J. of Inorganic Biochemistry(1994) vol. 56(2):97-116.
Yuen, Violet G., et al., “Glucose-Lowering Properties of Vanadium compounds: Comparison of Coordination Complexes with Maltol or Kojic Acid as Ligands,”J. of Inorganic Biochemistry(1997) vol. 68(2):109-116.
Welch, Inorg. Chem 27, 2862, 1988.*
Chauhan, Annali di Chimica 81, 179, 1991.
McNeill John H.
Melchior Marco
Orvig Chris
Berch Mark L.
Bozicevic Field & Francis LLP
Sherwood Pamela J.
The University of British Columbia
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