Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Reexamination Certificate
1998-04-22
2001-05-15
Lambkin, Deborah C. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
C514S184000, C514S185000, C514S186000, C514S187000, C514S188000, C546S002000, C546S006000, C546S010000, C549S206000, C549S210000, C549S212000
Reexamination Certificate
active
06232340
ABSTRACT:
TECHNICAL FIELD
This invention relates to vanadium(V) complexes, more specifically to hydroxyoxovanadium(V), p-oxo dimeric oxovanadium(V) and cis-dioxovanadium(V) complexes, to methods for synthesizing such complexes and to the use of such complexes as therapeutic agents.
BACKGROUND OF THE INVENTION
Vanadium complexes have been reported to have therapeutic properties. See, e.g., C. E. Heylinger et al.,
Science
227:1474, 1985; Y. Shechter,
Diabetes
39:1, 1990; C. Orvig et al.,
Metal Ions in Biol. Syst.
31:575, 1995); U.S. Pat. No. 5,527,790 by McNeill et al.; PCT published application WO 93/06811; C. Djordjevic,
Metal Ions Biol. Syst.
31:595, 1995; T. F. Cruz et al.,
Mol. Cell. Biochem.
153:161, 1995; H. Thompson et al.,
Carcinogenesis
5:849, 1984; C. Djordjevic et al.,
J. Inorg. Biochem.
25:51, 1985; PCT published application WO 95/19177; U.S. Pat. Nos. 5,583,242 and 5,565,491; P. Caravan et al.,
J. Am. Chem. Soc.
117:12759, 1995; Y. Sun et al.,
Inorg. Chem.
35:1667, 1996; and PCT published application WO 95/20390.
However, there remains a need in the art therapeutic agents having enhanced efficacy, stability, and/or ease of synthesis, etc. The present invention is directed to meeting this need and provides additional related advantages as disclosed herein.
SUMMARY OF THE INVENTION
The present invention is directed to vanadium(V) complexes, including pharmaceutically acceptable salts thereof, of the formula:
wherein,
Z
1
is independently selected from O and NR
4
;
Z
2
is independently selected from O and NR
5
;
Z
3
is independently selected from O, NR
6
and C(R
7
)
2
;
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are each independently selected from H, C
1
-C
10
alkyl, substituted C
1
-C
10
alkyl, C
7
-C
15
aralkyl, substituted C
7
-C
15
aralkyl, C
7
-C
15
alkylaryl, substituted C
7
-C
15
alkylaryl, C
6
-C
10
aryl, and substituted C
6
-C
10
aryl, such that independently R
1
and R
2
, and R
1
and R
4
, may together form a C
7
-C
15
alkylaryl, substituted C
7
-C
15
alkylaryl, C
6
-C
10
aryl, and substituted C
6
-C
10
aryl, wherein a substituted alkyl, aralkyl, alkylaryl or aryl contains at least one substituent selected from hydroxyl, fluoro, bromo, chloro, and iodo;
A is selected from —OH, ═O and
wherein Z
1
, Z
2
, Z
3
, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are each defined as above; and
a ring which includes Z
3
also contains two normalized bonds. The compounds of the present invention include pharmaceutically acceptable solvates or hydrates thereof. The present invention is further directed to compositions containing the above-listed vanadium complexes. An exemplary composition of the invention is a pharmaceutical composition containing one or more vanadium(V) complex as set forth above in admixture with a pharmaceutically acceptable carrier, diluent or excipient.
In another embodiment, the present invention is directed to a method of providing therapeutic treatment to an animal subject in need thereof. According to the inventive method, a therapeutically effective amount of one or more of the vanadium (V) complexs as identified above is administered to a subject in need thereof. Examples of such therapeutic treatments include treatment of proliferative disorders, bone destruction, metastases, drug resistant tumors, arthritis, psoriasis, multiple sclerosis, diseases involving a passageway of the subject's body, diabetes, diseases of the eye, diabetes-related metabolic complications, such as retinopathy, nephropathy and vasculopathy, hypertension, obesity, chronic inflammatory autoimmune disease, cardiovascular disease, lupus, bacterial infections, joint prostheses failure, periodontal disease, Inflammatory Bowel Disease (IBD), and treatment or prevention of surgical adhesions.
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patent: 5866563 (1999-02-01), McNeil et al.
patent: 5871779 (1999-02-01), Cruz
patent: WO 93/06811 (1993-04-01), None
patent: WO 95/20390 (1995-08-01), None
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Caravan et al., “Reaction Chemistry of BMOV, Bis(maltolato)oxovanadium(IV)-A Potent Insulin Mimetic Agent,”J. Am. Chem. Soc. 117(51): 12759-12770, 1995.
Chauhan and Kakkar, “3-Hydroxyflavone as a Reagent for the Microdetermination of Vanadium,”Annali di Chimica 81:179-183, 1991.
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Kohara et al., “Spectrophotometric determination of vanadium(V) by solvent extraction with 3-hydroxyflavone,”Japan Analyst 16: 315-322, 1967. (+English Translation).
Stewart and Porte, “Electron Paramagnetic Resonance Spectra of Some Oxovandium(IV) Chelates,”J. Chem. Soc., Dalton Trans 15: 1661-1666, 1972.
Wang et al., “Complexes of vanadium(V), molybdenum(VI) and tungsten(VI) with quercetin,”Inorganic Chem. vol. 112: p. 899, Abstract No. 90318t, 1990. (+Wang et al., “Investigation on the Complexes of V(V), Mo(VI) and W(VI) with Quercetin,”Chinese Journal of Applied Chemistry 6(4): 65-68, 1989.)
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Lemieux Pierre M.
Toleikis Philip M.
Zhang Zaihui
Angiotech Pharmaceuticals Inc.
Lambkin Deborah C.
Seed Intellectual Property Law Group PLLC
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