Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-06
2004-08-24
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S185000, C514S501000, C544S088000, C548S300100
Reexamination Certificate
active
06780856
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods of stabilizing in an aqueous medium cobalt (III) Schiff base complexes and stabilized cobalt (III) Schiff base compounds therefrom.
BACKGROUND OF THE INVENTION
Certain Schiff base cobalt complexes that exhibit antiviral, antitumor, and antimicrobial activities, as well as showing use in the treatment of inflammation and burns activity are stable for prolonged periods in solid form, but lose activity in aqueous solutions. The loss of activity in aqueous solutions results in loss of efficacy and a shorted shelf life.
A change in composition is responsible for the loss in compound efficacy and activity. When the complexes are in aqueous solutions without additives with good coordinating abilities, complexes such as [Co(acacen)L
2
]
+
, where acacen is 1,2-bis-acetylacetonate-ethylenediimine, L is NH
3
or 2-methylimidazole, show axial ligand exchange on the cobalt.
Accordingly, there is a need for methods of stabilizing Schiff base cobalt complexes in aqueous solutions. The stabilized compounds produced by invention methods are useful antiviral, antitumor, antinflammatory and antimicrobial agents.
SUMMARY OF THE INVENTION
In accordance with these objects, compositions are provided comprising water soluble tetradentate Schiff base complexes of Co(III).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to methods of stabilizing Cobalt(III) Schiff base complexes in aqueous media. Invention methods include obtaining Schiff base complexes and adding to the complex a linker or a chelator that binds to at least one axial ligand position of the complex.
As used herein, “Schiff base” refers to a substituted imine. Substituent groups are described herein. Schiff bases are generally the condensation products of amines and aliphatic aldehydes forming azomethines substituted on the nitrogen atom. The cobalt compounds of the invention utilize Co(III) (also depicted herein as Co+3). Co(III) compounds have up to six coordination atoms of which two are defined herein as axial ligand positions (L).
As used herein, “axial ligand position” refers to a ligand position (L) located at the fifth and sixth coordination sites, generally depicted in Structure A below.
Cobalt compounds of the invention derive their biological activity by the substitution or addition of ligands in the axial positions. Preferred ligands in the axial ligand position are nitrogen containing compounds including primary, secondary amines. Exemplary amines include NH
3
and heterocyclic nitrogen containing compounds such as substituted and unsubstituted imidazole.
Co(III) Schiff base complexes are stabilized by adding a linker that connects an axial ligand to an atom in the frame of the Schiff base complex. Linker atoms in the frame include atoms at R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
. Especially preferred linker atom sites are at R4 and R
5
, and preferred sites are at R
2
and R
3
. The resulting pentadentate cobalt compound has five axial ligand positions for binding. The complex thus formed remains monomeric, i.e., there is little or no intramolecule binding. This method makes it possible to increase the concentration of dissociated ligand around mono-aqua complexes.
As used herein, a “linker” refers to a molecule having that binds to more than one site on a complex wherein one site is an axial ligand position. When the linker is bound, a tether is formed that stabilizes the complex.
A linker of the present invention has the formula —(CH
2
)
n
—NR″R′″. Variable “n” can be 1, 2, 3, 4, 5, 6, 7 or 8, resulting in linker moieties of variable length. The length of the linker affects characteristics of the stabilized compound. The linker is able to disassociate at the axial ligand position. A shorter linker, for example when n is 1, 2, or 3, permits the tether to reassociate at the axial ligand position following disassociation more rapidly than when the tether is longer, for example, when n is 4 or 5. Disassociation and reassociation of the linker at the axial ligand position may permit or increase binding of the complex to its target (and thus have an affect on biological activity of the complex) if both axial ligand positions are binding sites that are essential for biological action. Disassociation and reassociation are also affected by the identity of R and R′.
In the linker, R″ and R′″ are independently selected from hydrogen and substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, ester, alkoxy, ether, or R and R′ can cooperate to form a substituted or unsubstituted heterocycle optionally having one or more double bonds. In preferred embodiments of the invention, R and R′ are both hydrogen. This embodiment is preferred because the bond at the axial ligand position is labile, allowing disassociation and reassociation of the linker. Synthesis of this linker can be readily accomplished by those of skill in the art. In another preferred embodiment, n is 2 and R and R′ cooperate to form an imidazole. In yet another preferred embodiment, n is 2 and R and R′ cooperate to form 2-methylimidazole.
By the term “tetradentate” herein is meant that the Schiff base complex, which is a ligand for Co(III), has four coordinating atoms. In a preferred embodiment, there are two nitrogen atoms and two oxygen atoms, which serve as coordinating atoms.
By the term “cobalt compound” herein is meant a tetradentate Schiff base complex with a bound cobalt atom. The Schiff base may be substituted or unsubstituted, and the cobalt is Cobalt (III) (Co(III)).
Also provided is a method of increasing the stability in aqueous media of a cobalt(III) Schiff base complex by obtaining a cobalt(III) Schiff base complex and contacting the complex with a chelator that connects first and second axial positions. The chelator can bind covalently to a Co(III) Schiff base complex.
As used herein, “chelator” refers to a compound having the structure:
wherein n is 2, 3, 4, 5, 6, 7, or 8. In especially preferred embodiments, n is 2, 3 or 4 and in preferred embodiments, n is 2, 3, 4 or 5.
In one embodiment of the invention, the first axial position and the second axial position are contained in the same Schiff base complex molecule resulting in intramolecular bonds. In another embodiment of the invention, the firs axial position is in a first Schiff base complex molecule and the second axial position is in a second Schiff base complex molecule resulting in intermolecular bonds. When there are intermolecular bonds, two or more molecules are connected by the chelator, resulting in dimers, i.e., two molecules connected by a linker, or resulting in oligomers, i.e., three or more moleucles connected by linkers. Dimers and oligomers can be connected by linkers that are bound at the same axial positions on each Schiff base complex, or that are bound at different axial positions on each Schiff base complex.
For most cobalt complexes, ligand exchange is a slow process because there is a large loss of ligand field stabilization energy when a ligand is removed from an octahedral d
6
complex (see Huheey et al., Inorganic Chemistry: Principles of Structure and Reactivity, 4th Ed. Harper Collins, N.Y., chapter 13). Generally, the exchange is slow; for example, [Co(III)(acacen)(NH
3
)
2
]Cl in water with excess imidazole exchanges ammonia for imidazole with a half-life under an hour at 25° C., with the rate of exchange increasing with temperature.
As used herein, “hydrocarbyl” refers to straight chain, branched chain and cyclic (i.e., ring-containing) monovalent and bivalent radicals derived from saturated or unsaturated moieties containing only carbon and hydrogen atoms. Straight and branched chain radicals have in the range of about 1 up to 12 carbon atoms and cyclic hydrocarbyl radicals have in the range of about 3 up to about 20 carbon atoms. The term “substituted hydrocarbyl” refers to hydrocarbyl mo
Blum Ofer
Gray Harry B.
Meade Thomas J.
California Institute of Technology
Gray Cary Ware & Freidenrich LLP
Patel Sidhaker B.
Shah Mukund J.
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