Dendrimeric compounds

• US 5,834,020 A
• Filed: 01/21/1997
• Issued: 11/10/1998
• Est. Priority Date: 04/20/1994
• Status: Expired due to Term

• Current Assignee: Amersham Health Salutar Incorporated (GE Healthcare Technologies, Inc.)
• Original Assignee: Nycomed Salutar, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Garrity, Martha, Campion, Brian, Fellmann, Jere Douglas, Margerum, Larry
• Primary Examiner(s): Levy, Neil S.
• Application Number:
  US08/722,082
• Time in Patent Office: 658 Days
• Field of Search: 424/DIG. 16, 424/484-489, 424/1.11, 424/1.33, 424/1.37, 424/9.1
• US Class Current: 424/484
• CPC Class Codes: A61K 2121/00 Preparations for use in therapy
• CPC Class Codes: A61K 2123/00 Preparations for testing in vivo
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/124 dendrimers, dendrons, hyperbranched compounds
• CPC Class Codes: A61K 51/065 conjugates with carriers being macromolecules
• CPC Class Codes: C08G 79/00 Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule
• CPC Class Codes: Y10S 424/16 Dendrimers and dendritic polymers

Abstract

The invention provides a dendrimeric compound comprising a dendrimeric bioactive moiety with linked thereto a plurality of diagnostically or therapeutically active moieties characterized in that the molecular skeleton of said compound contains at least one biodegradable cleavage site such that on cleavage thereof said active moieties are released in renally excretable form.

Claims

1. A dendrimeric compound or a salt thereof, said compound comprising a biodegradable core moiety and a dendrimeric backbone moiety, wherein said core moiety is a phosphazene or a boron-based core of the formula:

space="preserve" listing-type="equation">Y X-Y!.sub.q

in which X is carbon, oxygen, or nitrogen, each X, independently, is unsubstituted or substituted with R or Y'"'"'-X'"'"'!_q ;

Y is boron or phosphorus, each Y, independently, is unsubstituted or substituted with R or X'"'"'-Y'"'"'!_q ;

X'"'"' and Y'"'"' are as defined for X and Y, respectively, but cannot carry side chains Y'"'"'-X'"'"'!_q or X'"'"'-Y'"'"'!_q ;

each R, independently, is hydrogen, oxo, or a bond; and

q is 2-5; and

two non-adjacent Y groups can together represent a single Y group thereby, together with the intervening X and Y groups, creating a 4 to 10 membered ring; and

said backbone moiety has linked thereto a plurality of diagnostically or therapeutically active moieties, characterised in that the molecular skeleton of said compound contains at least one biodegradable cleavage site such that on cleavage thereof said active moieties are released in renally excretable form.

2. A compound as claimed in claim 1 wherein said active moieties comprise chelant moieties.

3. A compound as claimed in claim 2 wherein said active moieties comprise chelant moieties metallated with diagnostically or therapeutically effective metal ions.

4. A compound as claimed in claim 3 wherein said metal ions are selected from paramagnetic metal ions, heavy metal ions and ions of radionuclides.

5. A compound as claimed in claim 1 wherein said dendrimeric backbone is an up to eighth generation dendrimer.

6. A compound as claimed in claim 1 wherein said cleavage site of the backbone moiety is at a dendrimeric branching site.

7. A compound as claimed in claim 6 wherein said cleavage site comprises a polyatomic structure containing at least one atom other than carbon in its backbone.

8. A compound as claimed in claim 1 having at least one said cleavage site outside said dendrimeric backbone.

9. A compound as claimed in claim 1 which on biodegradation releases uniform renally excretable biodegradation products.

10. A compound as claimed in claim 1 further comprising at least one biodistribution modifying moiety attached to said molecular skeleton so as to enhance solubility of said compound, prolong the blood residence time of said compound, or direct said compound to desired tissue or body sites.

11. A compound as claimed in claim 10 wherein said biodistribution modifying moiety is tissue or body site-directing groups, which are molecules that naturally concentrate in a selected target organ, tissue, cell, or group of cells, or other location in a mammalian body, being selected from the group consisting of amino acids, oligopeptides, molecular recognition units, single chain antibodies, antibodies or fragments thereof, polysaccharides, collagen, bile acids, lipids and derivatives thereof, wheat germ agglutinin, complement components, complement component fragments, cytokines, eicosanoids, fibronectin, ferritin, transferrin, hemoglobin, epidermal growth factor, mannose-6-phosphate, ligands, lectins, asialofetuin, polyclonal immunoglobulin G, blood clotting proteins, lipoproteins, glycoproteins, hormones, growth factors, nucleic acids, deoxyribonucleic acids, antigens, haptens, clotting factors, polymerized fibrin fragments, serum amyloid precursor proteins, low density lipoprotein precursors, serum albumin, surface proteins of intact red blood cells, estrogens, galactosyl-neoglycoalbumin, N-(2-hydroxy-propyl)methacrylamide copolymers with bound galactosamines, allyl and 6-aminohexyl glycosides, fibrinogen, and a site-specific peptide, hydrophilic groups, lipophilic groups, and protein-binding inhibiting groups.

12. A compound as claimed in claim 11 wherein said biodistribution modifying moiety is a polyalkyleneoxide, modified polyethylene glycol, peptide or carbohydrate.

13. A compound as claimed in claim 1 having a molecular weight in the range 10³ to 10⁵ Daltons.

14. A process for the preparation of a compound as claimed in claim 1, said process comprising (i) conjugating a plurality of diagnostically or theraputically active moieties to a dendrimer;

or (ii) metallating chelant moieties linked to a dendrimeric backbone moiety with therapeutically or diagnostically effective metal ions.

15. A diagnostic or therapeutic composition comprising a dendrimeric compound as claimed in claim 1, or a salt thereof, together with at least one pharmaceutical carrier or excipient.

16. A method of generating an image of a human or non-human animal body which method comprises administering to said body an image enhancing amount of a dendrimeric compound as claimed in claim 1 or a salt thereof and thereafter generating an image of at least a part of said body.

17. A method of therapy of the human or animal body said method comprising administering to said body a therapeutically effective amount of a dendrimeric compound as claimed in claim 1.