Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfonic acids or salts thereof
Reexamination Certificate
1999-12-14
2001-08-21
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfonic acids or salts thereof
Reexamination Certificate
active
06278018
ABSTRACT:
TECHNICAL FIELD
The present invention relates to chemical compounds providing both charged groups as well as photoreactive species. In a related aspect, the invention relates to chemical compounds for use as surface coating agents.
BACKGROUND OF THE INVENTION
The chemical modification of surfaces to achieve desired chemical and/or physical characteristics has been previously described. For example, U.S. Pat. Nos. 4,722,906; 4,973,493; 4,979,959; 5,002,582; and 5,512,329 (each of which is commonly owned by the assignee of the invention described herein, and the disclosure of each is incorporated herein by reference), relate to surface modification by the use of latent reactive groups to achieve covalent coupling of reagents such as biomolecules and synthetic polymers to various substrates. The preferred latent reactive group is typically described as a photochemically reactive functional group (“photoreactive species”). When exposed to an appropriate energy source, a photoreactive species undergoes a transformation from an inactive state (i.e., ground state) to a reactive intermediate capable of forming covalent bonds with appropriate materials.
Such latent reactive groups can be used, for instance, to first derivatize a target molecule (e.g., thermochemically), in order to then photochemically attach the derivatized target molecule to a surface. Such a sequential approach is suitable in many situations, but can lack such attributes as speed, versatility, and ease of use, particularly when used with target molecules that are inherently difficult to first derivatize or under conditions that would result in loss of biological activity.
Latent reactive groups can also be used to prepare photoactivatable heterobifunctional molecules as linking agents, e.g., having a photoreactive species at one end or portion with a thermochemically attachment group at another (see, e.g., the above-captioned '582 patent, and U.S. Pat. No. 4,309,453, Reiner et al.). Such linking agents can be used to either attach nonreactive compounds to a surface or to prime a relatively inert surface in order to render it reactive upon exposure to suitable actinic radiation.
U.S. Pat. No. 5,414,075 (commonly owned by the assignee of the present invention and incorporated by reference herein), describes the use of linking agents to prime a surface to provide the surface with photoactivatable groups. This patent describes a restrained, multifunctional reagent useful for priming a support surface, or for simultaneous application with a target molecule to a support. Reagents such as those described above, including those described in the '075 patent, are generally hydrophobic. As a result, they are of relatively low solubility in aqueous systems, thereby often limiting their usefulness in hydrophilic applications.
U.S. Pat. No. 5,714,360, also commonly owned by the present assignee (and also incorporated herein by reference), describes a chemical linking agent comprising a di-or higher functional photoactivatable charged compound. The linking agent provides at least one group that is charged under the conditions of use, in order to provide improved water solubility, and two or more photoactivatable groups in order to allow the agent to be used as a linking agent in aqueous systems. The “Y group” that provides the core radical is defined as a radical containing one or more charged groups, such as the linear and heterocyclic nitrogen-containing (e.g., quaternary ammonium) radicals exemplified therein. In a preferred embodiment, the charged groups include, but are not limited to, salts of organic acids (such as sulfonate, phosphonate, and carboxylate groups), onium compounds (such as quaternary ammonium, sulfonium, and phosphonium groups), and protonated amines, as well as combinations thereof. The photoreactive species can be provided by two or more radicals of an aryl ketone such as benzophenone.
While the reagents of the art are sufficient, if not preferred, for many applications, there remain applications in which various other properties or attributes, such as water solubility, ease of synthesis and/or hemocompatability, are not optimally provided by the reagents of the art.
SUMMARY OF THE INVENTION
The present invention provides compounds useful as coating agents. In one aspect, the present invention provides a compound comprising a nonpolymeric core molecule comprising an aromatic group, the core molecule having attached thereto, either directly or indirectly, one or more substituents comprising negatively charged groups, and two or more photoreactive species, wherein the photoreactive species are provided as independent photoreactive groups. The first and second photoreactive species of the present coating agent can, independently, be identical or different.
In a preferred embodiment the reagent comprises a compound of the formula:
wherein X
1
comprises a first photoreactive species;
X
2
comprises a second photoreactive species;
Y comprises a nonpolymeric core molecule comprising an aromatic group; and
Z comprises at least one charged group.
In such an embodiment, for instance,Y can include an aromatic group such as a benzene radical, the charged groups Z can be independently selected from the salts of organic acids that include sulfonic acid, carboxylic acid, and phosphoric acid, and the photoreactive species of X
1
and X
2
can independently be aryl ketones, such as those selected from the group acetophenone, benzophenone, anthraquinone, anthrone, and anthrone-like heterocycles, and their substituted derivatives.
A coating agent of the invention has broad applicability, particularly since it can be used in surface modification reaction systems where previous agents have not been effective or optimal. In particular, the presence of one or more charged groups (e.g., salts of sulfonic, carboxylic and phosphoric acids) provides the agent with enhanced water solubility. This, in turn, allows the coating agent to be used in reaction systems favoring water soluble agents. A coating agent of the present invention thereby provides an improved combination of such properties as coating density and structural stability, allowing the agent to be used in a broad range of reaction systems.
Moreover, the presence of photoreactive species permits the agent to be used with a wide variety of support surfaces. The coating agent can be used alone as a coating composition for a support surface, in order to provide a surface primed with the coating agent itself. In this embodiment, the coating agent provides the surface with desirable properties of the coating agent itself, such as, for example, antithrombogenicity, lubricity, hemocomopatability, wettability/hydrophilicity, durability of attachment to the surface, biocompatability , and bacterial adhesion.
DETAILED DESCRIPTION
Compounds of this invention comprise a nonpolymeric core molecule comprising an aromatic group, the core molecule having attached thereto, either directly or indirectly, one or more substituenits comprising negatively charged groups, and two or more substituents comprising photoreactive species, wherein the photoreactive species are provided as independent photoreactive groups.
In a preferred embodiment, the core is provided as the residue of a polyhydroxy benzene starting material (e.g., formed as a derivative of hydroquinone, catechol, or resorcinol), in which the hydroxy groups have been reacted to form an ether (or ether carbonyl) linkage to a corresponding plurality of photogroups.
In one embodiment, a coating agent of this invention further comprises one or more optional spacers that serve to attach a core molecule to corresponding photoreactive species, the spacer being selected from radicals with the general formula:
—O—(CH
2
)
n
—, and
—(C
2
H
4
O)
m
—C
2
H
4
O—,
wherein n is a number greater or equal to 1 and less than about 5, and m is a number greater or equal to 1 and less than about 4.
In a particularly preferred embodiment, such coating agents are selected from the group 4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic a
Fredrikson & Byron , P.A.
Richter Johann
SurModics, Inc.
Witherspoon Sikarl A.
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