Compounds

• US 6,350,431 B1
• Filed: 10/28/1999
• Issued: 02/26/2002
• Est. Priority Date: 04/29/1997
• Status: Expired due to Term

• Current Assignee: GE Healthcare As (GE Healthcare Technologies, Inc.)
• Original Assignee: Nycomed A/S (Takeda Pharmaceutical Company Limited)
• Inventors: Desai, Vinay Chandrakant, Sanderson, William Anthony, Delecki, Daniel Joseph, Hohenschuh, Eric Paul, Bacon, Edward, Henrichs, Paul Mark, Snow, Robert Allen, Hollister, Kenneth Robert
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US09/429,347
• Time in Patent Office: 852 Days
• Field of Search: 424/9.6, 548/3, 548/223, 549/402, 549/455, 549/427
• US Class Current: 424/9.6
• CPC Class Codes: A61K 41/0033 Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds ultrasound therapy per se A61N7/00
• CPC Class Codes: A61K 41/0057 Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
• CPC Class Codes: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: A61K 49/0032 Methine dyes, e.g. cyanine dyes
• CPC Class Codes: A61K 49/0034 Indocyanine green, i.e. ICG, cardiogreen
• CPC Class Codes: A61K 49/0036 Porphyrins used in photodynamic therapy A61K41/0071 or A61K41/0076; used as targeting group or modifying agent for targeting a therapeutic compound A61K47/546
• CPC Class Codes: A61K 49/0041 Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal in vivo G01N
• CPC Class Codes: A61K 49/0043 Fluorescein, used in vivo
• CPC Class Codes: A61K 49/0052 Small organic molecules oligomers, polymers, dendrimers A61K49/0054
• CPC Class Codes: A61K 49/0054 Macromolecular compounds, i.e. oligomers, polymers, dendrimers
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: A61K 49/006 Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
• CPC Class Codes: A61K 49/0409 Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
• CPC Class Codes: A61K 49/0433 containing an organic halogenated X-ray contrast-enhancing agent
• CPC Class Codes: A61K 49/0466 Liposomes, lipoprotein vesicles, e.g. HDL or LDL lipoproteins, phospholipidic or polymeric micelles
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/126 Linear polymers, e.g. dextran, inulin, PEG
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

This invention provides a physiologically tolerable light imaging contrast agent compound having a molecular weight in the range 500 to 5000000 and containing at least two chromophores having delocalized electron systems as well as at least one polyalkylene oxide (PAO) moiety having a molecular weight in the range 60 to 100000.

Claims

1. A physiologically tolerable water-soluble light imaging contrast agent having a molecular weight in the range 500 to 500000 and containing at least two chromophores having delocalized electron systems that are linked to one polyalkylene oxide (PAO) moiety having a molecular weight in the range 60 to 100000.

2. A contrast agent as claimed in claim 1 wherein said PAO moiety has a molecular weight in the range 200 to 100000.

3. A contrast agent as claimed in claim 1 wherein said PAO moiety has a molecular weight in the range 250 to 50000.

4. A contrast agent as claimed in claim 1 wherein said PAO moiety has a molecular weight in the range 250 to 25000.

5. A contrast agent compound as claimed in claim 1 wherein said PAO moiety has a molecular weight in the range 400 to 15000.

6. A contrast agent as claimed in claim 1 wherein said chromophores are not lanthanide chelates unless said agent also comprises a chelated Tc, Sm, or Cu radionuclide.

7. A contrast agent as claimed in claim 1 wherein said PAO moiety comprises a block copolymer of polypropylene oxide and polyethylene oxide.

8. A contrast agent as claimed in claim 1 wherein said block copolymer is a linear polymer.

9. A contrast agent as claimed in claim 1 wherein said block copolymer is a branched polymer.

10. A contrast agent as claimed in claim 1 wherein said block copolymer is selected from the group consisting of Tetronic and Pluronic copolymers.

11. A contrast agent as claimed in claim 1 wherein said PAO moiety has a molecular weight in the range 1000 to 40000.

12. A contrast agent as claimed in claim 1 comprising at least three chromophores.

13. A contrast agent as claimed in claim 1 comprising at least four chromophores.

14. A contrast agent as claimed in claim 1 wherein the chromophores are selected from the group consisting of fluorescein, phthalocyanine and cyanine.

15. A contrast agent compound as claimed in claim 1 comprising moieties of formula I:

16. A contrast agent compound as claimed in claim 1 wherein the ratio of Chr:

PAO is greater than 1;

1.

17. A contrast agent compound as claimed in claim 1 comprising moieties of formula IV:

wherein

each L₁ is a group independently selected from the group consisting of an organic linker moiety and a chemical bond;

each X is independently selected from the group consisting of O, N-R₁, S, Se, Te, CH═

CH and (CH₃)₂C;

each R₁ is independently selected from the group consisting of a methyl group, an ethyl group, and a C_3-16 alkyl group optionally containing one or more heteroatoms selected from the group consisting of O, N, and S, which heteroatoms are separated from one another by at least 2 carbon atoms, and which ethyl and alkyl groups optionally contain one or more hydrophilic functional groups selected from the group consisting of hydroxyl groups, carboxyl groups, sulfonate groups, sulfate groups, phosphate groups, phosphonate groups, amino groups, amino acid groups;

each Z, of which there is at least one, is independently selected from the group consisting of H, a methyl group, an ethyl group as defined above, a C_3-16 alkyl group as defined above, a C_1-16 alkoxyl group, the alkyl portion of which is as defined above, a C_1-16 carboxyalkyl group, a C_1-16 oxycarbonylalkyl group, a sulfonate group, a hydroxyl group, a phosphate group, a C_1-16 sulfonamidoalkyl group, a phenyl-C_1-16-alkyl group, a phenoxy-C_1-16-alkyl group, a C_1-16 phenyloxyalkyl group, an oxyphenoxy-C_1-16-alkyl group, the alkyl portions each of which are as defined above, or an annulated aromatic ring which comprises a benz[e]aromatic ring, a benz[f]aromatic ring, or a benz[g]aromatic ring, each of which may be substituted by C_1-16 alkyl, C_1-16 alkoxyl, carboxyl, sulfonate, sulfonamido, phenyl, or phenoxyl groups as defined above;

each R₂ is independently selected from the group consisting of H, C_1-16 alkyl as defined above, or two R₂ groups together with the three intervening carbons form a 5 or 6 membered carbocyclic ring optionally containing a ring heteroatom selected from the group consisting of 0, N—

R₁ and S;

m is an integer up to 1200; and

each p independently is 0 or 1 when L₁ is an organic linker moiety.

18. A contrast agent compound as claimed in claim 1 comprising oligomeric moieties of formula V:

19. A contrast agent compound as claimed in claim 1 wherein the difunctional PAO moieties are selected from the group consisting of O-PEG-CH₂—

CH₂—

O, HN-PEG-CH₂—

CH₂—

NH, S-PEG-CH₂—

CH₂—

S, O-PEG-CH₂—

CH₂—

S, N-PEG-CH₂—

CH₂—

S and O-PEG-CH₂—

CH₂—

NH, wherein PEG moieties are poly(ethylene glycol) moieties derived from poly(ethylene oxide) and in which the molecular weight of any PEG moiety can be in the range from the molecular weight of monomeric ethylene diamine to about 100000.

20. A contrast agent compound as claimed in claim 1 wherein the molecular weight of the PEG moiety is in the range of 400 to 15000.

21. A contrast agent compound as claimed in claim 1 comprising at least two phthalocyanine chromophores linked to one polyalkyleneoxide moiety.

22. A contrast agent compound as claimed in claim 1 further comprising a targeting vector.

23. A contrast agent as claimed in claim 1 wherein said PAO moiety comprises a branched polyalkylene oxide.

24. A contrast agent compound as claimed in claim 1 comprising moieties of formula II:

25. A contrast agent compound as claimed in claim 1 comprising moieties of formula III:

26. A pharmaceutical composition comprising a physiologically tolerable light-imaging contrast agent compound as claimed in claim 1 together with at least one physiologically acceptable carrier or excipient, in a sterile, pyrogen free aqueous carrier medium.

27. A method of imaging of the human or animal (e.g. mammalian, avian or reptilian) body wherein a light imaging contrast agent as claimed in claim 1 is administered to said body and an image is generated by a light imaging modality of at least a part of said body to which said agent distributes, and wherein said modality is confocal scanning laser microscopy (CSLM), optical coherence tomography (OCT), photoacoustic, acousto-optical, diffusive wave, time-resolved imaging, endoscopic, multiphoton excitation microscopy or visual observation techniques.

28. A method as claimed in claim 27 wherein said part of said body is the sentinel lymph node.