Bisphosphonic acid derivative and compound thereof labeled...

Details Bisphosphonic acid derivative and compound thereof labeled... Bisphosphonic acid derivative and compound thereof labeled...

2000-10-12

2003-08-19

Jones, Dameron (Department: 1619)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001110, C424S001650, C424S009100

Reexamination Certificate

active

06607710

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a bisphosphonic acid derivative having an affinity to the bone, the bisphosphonic acid derivative labeled with a radioactive nuclide, a method for labeling the bisphosphonic acid derivative with the radioactive nuclide, and a radioactive agent for diagnosis or therapy of bone disease, containing the bisphosphonic acid derivative labeled with the radioactive nuclide as the active ingredient.
2. Related Art
In recent years, a scintigraphy of the skeleton in methods of nuclear medicine becomes one of the important test methods in its early stage for diagnosis of the bone disease. As to an imaging agent used for scintigraphy of the bone, said agent requires shorten intervals between the administration of the imaging agent and the timing of taking a scintigram, further such agent should have the properties of high affinity to the bone and of efficient urinary excretion, as well as rapid clearances from the blood and non-osseous tissues.
At present, a phosphonic acid derivative labeled with a radioactive isotope may be used for the above-mentioned purposes, and an inorganic polyphosphonic acid labeled with 99m-Technetium was used as the first example therefor. However, such inorganic polyphosphonic acids labeled with 99m-Technetium perform inevitably the lower clearance from the blood, because such compounds may be changed to the corresponding monophosphates by hydrolysis in aqueous solutions.
In order to solve such problems, Yano, et al. reported stannous Tc-99m-ethane-1-hydroxy-1,1-diphosphonate (Tc-99m-HEDP), which is an organic diphosphonic acid labeled with 99m-Technetium [J. Nucl. Med., 14, 73, (1973) and U.S. Pat. No. 3,735,001)]. By use of said compound, the bone scintigraphy can be carried out in the earlier stage of test after the compound is administered, because this compound has property of relatively rapid clearance from the blood. For this reason, compounds of phosphonic acid labeled with 99m-Technetium, which are compounds similar to Tc-99m-HEDP, for example compounds relating to organic diphosphonic acid, such as methanediphosphonic acid (MDP), 3,3-diphosphono-1,2-propanedicarboxylic acid (DPD) and hydroxymethanediphosphonic acid (HMDP) and the like, being labeled with 99m-Technetium are widely used for this purpose. These compounds are used for pharmaceutical preparations for bone scintigraphy, which can deposit or accumulate to the sites where calcification of the bone is taken place, and such compounds make an interval between the administration of the imaging agent and the timing of taking a scintigram shorten. However, these compounds are still not good enough in connection with the waiting time, because they require waiting time for about 3 hours after the administration of compound to take a scintigram.
Generally, in conducting a bone scintigraphy, when the radioactivity of imaging agent disappears slowly from the blood and/or soft tissue with the slower urinary excretion, then a certain length of time for lowering the background of radioactivity is required, and it is necessary to have the longer waiting time for taking a scintigram after the administration of imaging agent. When a phosphonic acid compound labeled with Technetium is used, the polymer structure thereof may be considered as one of the factors for giving influence on the clearance. The phosphonic acid compound labeled with Technetium may give high possibility of affecting the clearance due to the formation of polymer structure. Attempt at realizing the rapid clearance in the earlier stage after the administration of an imaging agent by changing the polymer structure of the radiolabeled bisphosphonic acid compound to monomolecular structure has been made with a bisphosphonate compound labeled with 123-Iodine (WO 89/11877), but satisfactory result has not been obtained yet. When a possible coordination site for a radioactive metal, other than the phosphonic acid group, is introduced to a bisphosphonate compound, the compound labeled with a radioactive metal might give a stable monomolecular structure. However, such trial described above with available compounds for use in bone scintigraphy has not been carried out and, of course, properties of the resultant monomolecular compound as a bone imaging agent have not been examined.
Under the circumstances, an object of the present invention is to provide a bisphosphonic acid derivative having the properties of rapid accumulation to the bone and rapid urinary excretion, and a compound thereof labeled with a radioactive nuclide.
SUMMARY OF THE INVENTION
The present invention provides a bisphosphonic acid derivative or salt thereof represented by the following formula (1):
R—Y—A  (1)
wherein A is a bisphosphonic acid or salt thereof, having a P—C—P bond; Y is a bonding portion selected from the group consisting of —(CH
2
),—, —[(CH
2
)
m
(NHCO)
r
(CH
2
)
n
]
q
—, —[(CH
2
)
m
(CONH)
r
(CH
2
)
n
]
q
— and —(CH
2
)
o
—S—(CH
2
)
p
—; k, l, m, n, o, p, q, and r are each represents independently an integer, and k=0 or 1; l=0 to 6; m=0 to 6; n=1 to 6; o=0 to 6, p=0 to 6; q=1 to 6; and r=1 to 6; R is a group of any one of compounds selected from the group consisting of a polyaminopolycarboxylic acid, an aliphatic carboxylic acid, a mercaptoacetylpolyamino acid or its derivative and a compound represented by the following formula (2),
and in the formula (2), X is a halogen atom or its isotope, or alkyl tin; Z is a group of any one of compounds selected from the group consisting of an aminocarboxylic acid, an alkylcarboxylic acid, a substituted-alkylcarboxylic acid, an alkylsulfonic acid and a substituted-alkyl sulfonic acid.
A radiolabeled bisphosphonic acid derivative prepared by labeling the above-mentioned bisphosphonic acid derivative with a radioactive nuclide is useful as an active ingredient of radiopharmaceutical for the bone scintigraphy or the bone disease therapy, and as to preferable radioactive nuclides, 99m-Technetium, 111-Indium, 117m-Tin, 153-Samarium, 186-Rhenium, 188-Rhenium, 123-Iodine, 125-Iodine, 131-Iodine, 211-Astatine and the like can be exemplified.
The above-mentioned bisphosphonic acid derivative labeled with radioactive nuclide represented by the formula (1), wherein R is a group being labeled with radioactive halogen or a radioactive transition metal; and A is a free form of bisphosphonic acid or salt thereof without participating in the formation of complex with said radioactive transition metal or other metal, is one of the embodiments of the present invention and is useful as the active ingredient of a radiopharmaceutical for the bone scintigraphy or the bone disease therapy.
Another embodiment of the present invention is, in case of labeling the bisphosphonic acid derivative with a radioactive transition metal, a labeling method that a bisphosphonic acid derivative is allowed to react with a peracid ion of radioactive transition metal in the presence of non-metallic reducing agent to form a complex.
Preferably, said peracid ion of the radio-active transition metal is selected from any one of the group consisting of pertechnetate (Tc-99m), perrhenate (Re-186), and perrhenate (Re-188); and the non-metallic reducing agent is selected from any one of the group consisting of sodium diphenylphosphinobenzene-3-sulfonate, formamidinesulfonic acid and glucoheptanoic acid.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides, as represented by the above-mentioned formula (1), a bisphosphonic acid derivative wherein a bisphosphonic acid having the affinity to the bone is combined with a group capable of being labeled with a radioactive transition metal or a radioactive halogen. The bisphosphonic acid derivative having the affinity to the bone can be used as the active ingredient of agent for diagnosis or therapy of bone disease by radiolabeling.
In the formula (1), A is alpha-geminal-bisphosphonic acid, i.e., bisphosphonic acid having P—C—P bon

Affiliated with

Also associated with

Rating

Bisphosphonic acid derivative and compound thereof labeled... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Bisphosphonic acid derivative and compound thereof labeled..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bisphosphonic acid derivative and compound thereof labeled... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3086989