Compounds

Details Compounds Compounds

1999-10-28

2002-02-26

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Diagnostic or test agent produces in vivo fluorescence

C548S559000, C548S223000, C549S402000, C549S427000, C549S455000

Reexamination Certificate

active

06350431

ABSTRACT:

This invention relates to compounds useful as contrast agents in light imaging procedures, in particular compounds containing a plurality of chromophores as well as one or more hydrophilic polyalkylene oxide (PAO) moieties.
The use in diagnostic imaging procedures of materials (contrast agents) which enhance image contrast is well established.
In light imaging procedures, the contrast agents will generally act as light scatterers or as light absorbers or emitters. The present invention is concerned with contrast agents which contain chromophores and thus absorb or emit light.
As used in this application, “light imaging” refers to diagnostic procedures that result in an image of the interior of the body or of the surface of the body by a process involving propagation through or reflection from the body of electromagnetic radiation with a wavelength in the range 300 to 1300 nm. The propagating electromagnetic radiation can result either from irradiation of the body or a portion of the body with light in the specified wavelength range or by generation of light within the wavelength range in the body or on the surface of the body by processes such as bioluminescence, sonoluminescence, or fluorescence.
The propagating light can be detected directly with sensors at the surface or within the body or indirectly after the generation from the light of another form of energy such as sound, ultrasound, heat, or electromagnetic radiation outside of the wavelength range 300 to 1300 nm. A sensor is a device that converts the detected light, sound, ultrasound, heat or other form of signal into a recordable form such as electrical current. An example of a light sensor is a photomultiplier tube. A sensor for light may also consist of a fiber-optic cable leading from the point of detection to a photomultiplier tube. In a simple embodiment of light imaging the sensor consists of the human eye.
By chromophore is meant a group in a composition of matter, eg. an organic or inorganic group which absorbs and/or emits light. The term thus includes fluorophores, groups which are fluorescent, as well as phosphorescent groups. In general chromophores will contain a complexed metal ion or an extensive delocalized electron system. One aspect of the present invention is particularly concerned with the latter type. A compound containing a chromophore is sometimes herein referred to as a chromophore.
By light is meant electromagnetic radiation having wavelengths from 300-1300 nm. Chromophores having absorption and/or emission maxima in the visible to far infra-red range are particularly relevant to the invention.
While certain small organic chromophore-containing molecules, such as indocyanine green, have been used as contrast agents in light imaging procedures, their utility is limited as they are relatively rapidly cleared from the blood stream and hence provide a relatively short or narrow imaging window.
It is thus an objective of the invention to provide light imaging contrast agents which provide the user with an extended imaging window and thus are suitable for example for studies of blood flow, of perfusion of effusion, and of the vascularization of sites of interest.
Thus viewed from one aspect the invention provides a physiologically tolerable water-soluble light imaging contrast agent compound having a molecular weight in the range 500 to 500000 and containing at least two chromophores having delocalized electron systems as well as at least one polyalkylene oxide moiety having a molecular weight in the range 60 to 100000, preferably 200 to 100000, more preferably 250 to 50000, especially preferably 250 to 25000 and more especially preferably 400 to 15000, and preferably wherein said chromophores are not lanthanide chelates unless said agent also comprises a chelated Tc, Sm, or Cu radionuclide, and more preferably said chromophores are not chelated lanthanides.
The polyalkylene oxide PAO moiety can be linear or branched and is preferably a homopolymeric or copolymeric, especially block copolymeric, moiety containing repeat units C
n
H
2n
O where n is 2,3 or 4, preferably 2 or 3, especially preferably CH
2
CH
2
O, OCHCH
3
CH
2
, CH
3
CHCH
2
O or CH
2
CH
2
CH
2
O repeat units. Within the PAO moiety, one or more, preferably one or two, of the ether oxygens may be replaced by an amine group NH or NE where E is a bond or an alkyl or hydroxyalkyl group or a (C
n
H
2n
O)
q
E′ side chain (where n is 2,3 or 4 and q is an integer, the maximum value for which is set by the molecular weight limit for the PAO and E′ is H or alkyl, a chemical bond or a chromophore).
Any alkyl, alkenyl or alkynyl moieties, unless otherwise defined, preferably have up to 12, especially preferably up to 6 carbons.
The compounds of the invention preferably have a polymer structure with repeat units containing both a chromophore and a polyalkylene oxide moiety. At the lower limit of such a polymer structure, the compounds may simply contain two chromophores and a polyalkylene oxide moiety. The compounds of the invention may thus be of or contain a moiety of formula I
Chr-L[PAO-L-Chr]
n
  (I)
where
each Chr which may be the same or different is a chromophore,
each PAO which may be the same or different is a polyalkylene oxide moiety,
each L is a bond or organic linking group connecting at least one PAO to at least one Chr, and
n is an integer having a value of at least 1 (the upper limit for n being determined by the molecular weight limit for the compounds of the invention).
As used herein, the term “linking group” is a chemical moiety that connects together at least two molecules, at least the residue of one molecule with another molecule, or at least the residue of one molecule with the residue of another molecule.
The unit [PAO-L-Chr] will allow for the polymer to be branched or alternatively to be linear. Examples of such structures include:
where L′ and L″ are bonds or linker groups as mentioned above. Thus, when [PAO-L-Chr] is a repeat unit in a polymer, the PAO and Chr moieties may form part of or may be pendant from the polymer backbone. Similarly the repeat unit [PAO-L-Chr] may contain more than one chromophore or more than one PAO moiety.
Alternatively the compounds of the invention may comprise a branched polymer, such as a dendrimer or cascade polymer, with PAO and Chr moieties attached to polymer termini. As used herein, a branched polymer is a polyalkylene oxide moiety which contains at least one branching group to which is attached at least one additional polyalkylene oxidyl group.
In one aspect, a branching group in the backbone of the polyalkylene oxide moiety can be selected from the group consisting of a nitrogen atom and a carbon atom. At least one additional polyalkylene oxidyl group can be attached to the branching group by a chemical bond selected from the group consisting of carbon-carbon, carbon-nitrogen, and carbon-oxygen chemical bonds, or by a linking group.
Preferred linking groups to a nitrogen branching group include:
methylene groups, [—CH
2
—];
poly(methylene) groups, [—(CH
2
)
n
—] wherein n is an integer from 2 to about 16, such as can be formed by reaction between a nitrogen NH group and an alkylenyl group containing a terminal halide (e.g., Cl, Br, I) or sulfonate group (e.g., methanesulfonate, toluenesulfonate, benzenesulfonate and the like);
alkylenecarbonyl groups [—(CH
2
)
n″
—C(═O)—] wherein n″ is an integer from 1 to about 16 such as can be formed by reacting an NH group with a haloalkylenecarbonyl group;
ethylenesulfonylethylene groups [—CH
2
CH
2
—S(═O)
2
—CH
2
CH
2
—], such as can be formed by reacting an NH group with a vinylsulfonylethylene group [CH
2
═CH—S(═O)
2
—CH
2
CH
2
—];
ethylenesulfonylmethyleneoxymethylenesulfonylethylene groups [—CH
2
CH
2
—S(═O)
2
—CH
2
—O—CH
2
—S(═O)
2
—CH
2
CH
2
—], such as can be formed by reacting an NH group with a vinylsulfonylmethyleneoxymethylenesulfonylethylene group [CH

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