Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2000-12-18
2003-09-23
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001110, C424S001370, C424S009100, C424S009200, C558S017000
Reexamination Certificate
active
06623721
ABSTRACT:
FIELD OF THE INVENTION
This application is directed to new types of hydroxamic acid-based bifunctional chelators. These chelators preferably chelate metal ions that can be detected either by their paramagnetic or radioactive properties.
BACKGROUND OF THE INVENTION
Natural substances containing hydroxamic acid functionalities in their structures exhibit a wide variety of biological activities. Frequently, they act in vivo as antibiotics, growth factors, and iron-transport agents. Siderophores represent one type of natural substance that contain hydroxamic acid functionalities. Siderophores are small iron-chelating molecules produced by the organism when iron deficiencies occur. There are mainly two classes of siderophores, the cathecolamides and the hydroxamates. The cathecolamide class includes, for example, parabactin and vibriobactin. The hydroxamate class includes, for example, bisucaberin (macro-cyclic), desferrioxamine B (linear), desferrioxamine G (linear) and desferrioxamine E (macrocyclic). Because of their numerous potential applications, such as in the treatment of iron overload, also known as Cooley's anemia, as contrast agents for NMR imaging, and as diagnostic and therapeutic radiopharmaceuticals, the design and synthesis of new chelators possessing hydroxamic acid residues have attracted the attention of several research groups.
OBJECTS OF THE INVENTION
It is one object of this invention to provide chelators that can be attached to peptides and proteins by forming a thiourea or amide bond.
It is a further object of this invention to provide compounds that include diagnostic and therapeutic agents.
It is yet another object of this invention to provide improvements in research and diagnostic methods and materials for assaying bodily states in animals, especially disease states.
BRIEF DESCRIPTION OF THE INVENTION
These and other objects are satisfied by the present inventions, which in one aspect provide chelators that can be attached to peptides or proteins. The chelators of the invention generally possess hydroxamic acid functionalities and can be bound to peptides and/or proteins, by forming a thiourea or amide bond. Preferred chelators have any of the formulas I, II, or III:
where n, m and o are, independently, an integer from 1 to about 4;
X is CH
2
, nitrogen (N(R
4
)), oxygen or sulfur;
Y is hydrogen, —OH (hydroxyl),═O (carbonyl), N(R
4
)(R
5
), or ═S;
R
1
is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group;
R
2
is an active group such as an activated ester, a carboxylic acid, an alkyl isothiocyanate, an aromatic isothiocyanate or a leaving group (such as I, Br, Cl, F, mesylate, tosylate, trifluorosulfonate (triflate);
R
3
is hydrogen or a protective group;
R
4
is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group;
R
5
is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group;
Z
1
is hydrogen, nitrogen, oxygen, or sulfur;
Z
2
is hydrogen, nitrogen, oxygen, or sulfur;
In preferred embodiments, the activated ester is one of the following:
The carboxylic acid group can be preferably:
The isothiocyanato group preferably is one of the following:
and the protective group preferably is:
In another aspect, the present inventions also provide methods for diagnosis and treatment of receptor-positive tumors. Once linked to biologically active ligands, the conjugates can be complexed to a radioisotope metallic element and used for diagnosing or treating any appropriate receptor-positive tumors.
REFERENCES:
patent: 4256765 (1981-03-01), Munakata et al.
patent: 4741887 (1988-05-01), Coleman et al.
patent: 5539138 (1996-07-01), Flanagan et al.
patent: 5556939 (1996-09-01), Flanagan et al.
patent: 5632969 (1997-05-01), Flanagan et al.
patent: 5733342 (1998-03-01), Greindl et al.
patent: 5756825 (1998-05-01), Safavy et al.
patent: WO 92/20227 (1992-11-01), None
patent: WO 93/00082 (1993-01-01), None
patent: WO 94/05627 (1994-03-01), None
Altenburger, J.M., et al., “Useful hydroxylamine derivatives for the synthesis of hydroxamic acids,” Received in France Mar. 20, 1992, 5055-5058.
Atherton, E., et al., “Peptide synthesis. Part 10. Use of pentafluorophenyl esters of fluorenyl methoxycarbonylamino acids in solid phase peptide synthesis,”Tetra. Letts.,1988, 44(3), 843-857.
Bergeron, R,J., et. al., “Synthesis and biological evaluation of hydroxamate-based iron chelators,”J. Medicinal Chem.,1991, 34, 3182-3187.
Bergeron, R.J., et al., “The total synthesis of desferrioxamines E and G,”Tetrahedron,1990, 46(17), 5581-5888.
Bergeron, R.J., et al., “The total synthesis of alcaligin,”J. Org. Chem.,1991, 56, 5560-5563.
Bergeron, R.J., et al., “The total synthesis of bisucaberin,”Tetrahedron,1989, 45(16), 4939-4944.
Carpino, L.A., et al., “O-Acylhydroxylamines. I. Synthesis of O-Benzoylhydroxylamine,”J. Am. Chem. Soc., 81,1959, 955-957.
Castro, J.L., et al., “Mitsunobu-like processes with a novel triphenylphosphine-cyclic sulfamide betaine,”J. Org. Chem.,1994, 59(9), 2289-2291.
Chaubet, F., et al., “The design of magnetic resonance contrast agents: new iron (III) dihydroxamate complexes,”Tetra. Letts.,1990, 31(40), 5729-5732.
Chaudhary, S.K., et al., “4-dimethylaminopyridine: an efficient and selective catalyst for the silyation of alcohols,”Pergamon Press Ltd.,1979, 20(2), 99-102.
Gibson, F.S., et al., “Selective removal of an N-BOC protecting group in the presence of a tert-butyl ester and other acid-sensitive groups,”J. Org. Chem.,1994, 59(11), 3216-3218.
Henry, J.R., et al., “Mitsunobu reactions of N-Alkyl and N-Acyl sulfonamides-an efficient route to protected amines,”Tetra. Letts.,1989, 30(42), 5709-5712.
Hou, Z., et al., “Preorganization of ferric alcaligin, Fe2L3-The first structure of a ferric dihydroxamate siderophore,”Am. Chem. Soc.,1996, 118(21), 5148-5149.
Huffman, W.F., et al., “Nuclear analogues of &bgr;-lactam antibiotics. 2. the total synthesis of 8-Oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acids,”J. Am. Chem. Soc.,1977, 99.7, 3 pages.
Iida, H., et al., “An efficient, fully stereocontrolled total synthesis of N-Benzoyl-L-daunosamine,”J. Org. Chem.,1986, 51(22), 4245-4249.
Karunaratne, V., et al., “General method for the synthesis of trishydroxamic acids,”Tetra. Letts.,1992, 33(14), 1827-1830.
Katoh, A., et al., “N-hydroxy amides. Part 9. Synthesis and iron (III) complexes of tripodal hydroxamic acids derived from &ohgr;-(N-Hydroxyamino)alkanoic acids and tris-(2-aminoethyl)amine,”J. Chem. Soc. Perkin Trans.,1991, 1839-1842.
Koshti, N.M., et al., “Convenient method for the preparation of some polyhydroxamic acids: Michael addition of amines to acrylohydroxamic acid derivatives,”Tetra. Letts.,1994, 35(29), 5157-5160.
Lee, B.H., et al., “Natural ferric ionophores: Total synthesis of schizokinen, schizokinen A, and arthrobactin,”J. Org. Chem.,1983, 48(1), 24-31.
Miller, M.J., “Hydroxamate approach to the synthesis of &bgr;-lactam antibiotics,”Acc. Chem. Res.,1986, 19, 49-56.
Nikam, S.S., et al., “Synthesis of hydroxamic acids: Pd/BaSO4as a new catalyst for the deprotection of o-benzyl hydroxamates,”Tetra. Letts.,1995, 36(2), 197-200.
Rajappa, S., et al., “Hydroxamic acids and their derivatives-III; Preparation of esters of pivalohydroxamic acid and their use in peptide synthesis,”Tetrahedron,1967, 23, 4805-4809.
Ramalingam, K., et al., “Syntheseis of nitroimidazole substituted 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioximes (propylene amine oximes, PnAOs): ligands for technetium-99m complexes with potential for imaging hypoxic tissue,”Tetrahedron,1995, 51(10), 2875-2894.
Safavy, A., et al., “Synthesis of N-[tris[2-[N-(benzyloxy)amino]carbonyl]ethyl]succinamic acid, trisuccin. Hydroxamic acid derivatives as a new class of bifunctional chelating agents,”Bioconjugate Chem.,1993, 4(3), 194-198.
Sandler, S.R., et al., “Chapter 12/Hydroxamic Acids,”Org. Functional Group Preparations,1972, 3, 406-447.
Spanevello, R.A., et al., “synthesis of novel, highly potent cyclic-hexapeptide analogs of somatostatin. Potential application of orthogonal protection
Dufour Jean-Marc
Flanagan Richard J.
Draximage, Inc.
Jones Dameron L.
Woodcock & Washburn LLP
LandOfFree
Bifunctional chelating compounds containing hydroxamic acid... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Bifunctional chelating compounds containing hydroxamic acid..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bifunctional chelating compounds containing hydroxamic acid... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3079202