Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2001-12-27
2004-08-17
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S009360, C424S009400, C558S166000, C514S143000
Reexamination Certificate
active
06776977
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a novel class of tripodal polyaminophosphonates and metal chelates thereof, methods of preparing the tripodal polyaminophosphonate chelants and metal complexes, and pharmaceutical compositions comprising the tripodal polyaminophosphonate chelants and metal chelates. This invention relates particularly to the use of the new metal chelates as contrast agents for x-ray or MRI imaging. This invention also relates to the use of metal chelates useful as diagnostic radiopharmaceuticals for imaging the skeleton, myocardial infarction, infarctions of the spleen and bowel, inflammatory bowel disease, radiation injury, metastastic calcification, bone cancer, and various bone disorders. This invention also relates to the use of radiometal chelates particularly useful as therapeutic radiopharmaceuticals for bone pain relief, bone marrow suppression, the treatment of bone cancer, and various bone disorders.
BACKGROUND OF THE INVENTION
The development of a bone metastasis is a common and often catastrophic event for a cancer patient. The number of patients with metastastic disease is large among those who have breast cancer, prostate cancer, and lung carcinoma, as well as other tumors (Bouchet, L. G., et al.
J. Nucl. Med.
2000, 41, 682-687). The pain, pathological fractures, frequent neurological deficits and forced immobility caused by these metastastic lesions significantly decreases the quality of life for cancer patient. The initial goal for the treatment is to relieve the pain, reduce narcotic medication requirement, and increase ambulation.
The use of radionuclides for the treatment of metastastic cancer started in the early 1950's. It has been proposed that a radionuclide, particularly □-emitters, could be concentrated in the fast growing portion of the bone with minimal amounts of radiation reaching the soft tissue or normal bone. Over the years, treatment of bone pain using bone-seeking radiopharmaceuticals has been explored extensively. The use of radiopharmaceuticals which cause partial or total suppression or eradication of the bone marrow has become an accepted part of procedures used to treat a patients with cancer such as leukemias, lymphomas, myelomas and Hodgkin's disease as well as in the treatment of patients suffering from genetic disorders such as sickle cell anemia and thalassemia. Details on the use of therapeutic radiopharmaceuticals for bone pain palliation and treatment of bone metastases can be found in the following references: Stanley, I. K. et al.
Anticancer Res.
1988, 8, 681-684; Serafini, A. N.
J. Radiation Oncol. Biol. Phys.
1994, 30, 1187-1194; McEwan, A. J. B.
Semin. Nucl. Med.
1997, 27, 165-182; Krishnamurthy, G. T. and Krishnamurthy, S.
J. Nucl. Med.
2000, 41, 688-691; Bouchet, L. G., et al.
J. Nucl. Med.
2000, 41, 682-687.
32
P-labeled orthophosphate (Silberstein, E. B.
Semin. Oncol.
1993, 20, 10-20) and
89
SrCl
3
(Ackey, D. and Yardly, J.
Semin. Oncol.
1993, 20 (suppl.), 27-31) are the first radiopharmaceuticals to be evaluated for this purpose. U.S. Pat. No. 4,399,817 discloses the use of phosphorus compounds containing a boron residue. The compounds were injected into the body and accumulated in the skeletal system. The patient was then irradiated with neutrons in order to activate the boron, and to give a radiation dose.
The drawback associated with
32
P and
89
Sr as palliative agents is that both isotopes are high-energy □-emitters with very long penetration range, which can result in significant irradiation of the marrow compartment and depression of normal bone function. Therefore, it is impossible to give therapeutic doses to the tumor without substantial damage to normal bone and soft tissues.
Polyaminophosphonate chelants show very high affinity for hard cations such as Ca
2+
and lanthanide metal ions. Metal chelates of polyaminophosphonates often localize in bone in a short period of time, probably in part due to interactions of the uncoordinated oxygen donors in the polyaminophosphonate chelate with Ca
2+
on the bone surface. Due to their high bone uptake, radiometal chelates of polyaminophosphonate chelants have been studied as therapeutic radiopharmaceuticals for bone-pain palliation and for the treatment of bone cancer metastasis. European patent application No. 291,605 and U.S. Pat. No. 4,898,724 disclose the use of Sm-153, Gd-159, or Ho-166 chelates for bone marrow suppression. The lanthanide chelate contains a linear polyaminophosphonate chelant selected from ethylenediaminetetramethylenephosphonic acid (EDTMP), diethylenetriaminepentamethylenephosphonic acid (DTPMP), hydroxyethylethylenediaminetrimethylenephosphonic acid (HEEDTMP), nitrilotrimethylenephosphonic acid (NTMP), or tris(2-aminoethyl)aminehexamethylenephosphonic acid (TTHMP). U.S. Pat. No. 4,882,142 discloses the use of Sm-153, Gd-159, or Ho-166 chelates with 1,4,7,10-tetraazacyclododecane-tetramethylenephosphonic acid (DOTMP) for bone marrow suppression and other bone-related diseases. The chelate
153
Sm-EDTMP (Quadramet®) has recently been approved by FDA for bone pain palliation. The chelate
166
Ho-DOTMP is under clinical investigation for both bone pain palliation and the treatment of bone metastases. Despite their success, there is still a need for a better therapeutic radiopharmaceutical labeled with an appropriate lanthanide radionuclide.
Prior to therapy it is necessary to obtain reliable diagnostic information and to this end several approaches have been tried. It is known that phosphates and phosphonates have an affinity for hydroxyapatite crystals, and tend to localize in vivo in the regions of bone metabolism, and in certain tumors, such as neuroblastoma. The uptake of radiopharmaceuticals containing phosphonate chelant in tumors is attributed to calcification in tumors. For example, U.S. Pat. No. 3,974,268 discloses the use of technetium-99m (
99m
Tc) chelates of diphosphonate chelants as skeletal imaging agents. The diphosphonate is used as both the bone targeting-agent and the chelating agent for
99m
Tc. The properties of these radiopharmaceuticals, which lead to their localization in bone, also allow for them to localize in soft tissues bearing recognition features in common with bone. Localization of such agents in areas of myocardial infarction is an example of one application, which has proven diagnostically useful. Radiopharmaceuticals, which localize in bone, also have been shown to localize infarctions of the spleen and bowel, inflammatory bowel disease, radiation injury, as well as metastastic calcification.
Radionuclides, including but not limited to
99m
Tc,
117m
Sn,
111
In,
67
Ga,
68
Ga,
89
Zr,
62
Cu,
64
Cu and
67
Cu, have been proposed for diagnostic imaging. The choice of the radionuclide depends largely on the physical and nuclear properties (half-life and □-energy), availability, and cost. In general, generator-produced radionuclides are considered ideal, since the generator system consists of a long-lived parent isotope that decays to a short-lived daughter isotope. The daughter can be easily separated from the parent by either ion-exchange chromatography or solvent extraction.
Nearly 80% of radiopharmaceuticals used in nuclear medicine are
99m
Tc-labeled compounds. The reason for such a preeminent position of
99
mTc in clinical use is its extremely favorable physical and nuclear characteristics. The 6 h half-life is long enough to carry out radiopharmaceutical synthesis and to collect useful images. At the same time, it is short enough to permit the administration of millicurie amounts of
99m
Tc radioactivity without significant radiation dose to the patient. The monochromatic 140 KeV photons are readily collimated to give images of superior spatial resolution. Furthermore,
99m
Tc is readily available from commercial
99
Mo—
99m
Tc generators at low cost.
Various
99m
Tc-labeling techniques have been described in several reviews (Liu, S. and Edwards, D. S.
Chem. Rev.
1999, 99, 2235-2268; Jurisson, S. and Lydon, J. D
Bristol-Myers Squibb Pharma Company
Hartley Michael G.
Volles Warren K.
Woodcock & Washburn LLP
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