Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1999-06-17
2001-08-07
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001650, C424S001690, C424S001730, C534S010000, C534S014000
Reexamination Certificate
active
06270745
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a radioactive transition metal nitride heterocomplex, a radiopharmaceutical comprising said complex, and a process for producing said complex. More particularly, the present invention relates to a radioactive transition metal nitride heterocomplex comprising a nitride of radioactive technetium or radioactive rhenium and two different ligands coordinated therewith, a radiopharmaceutical for diagnostic imaging or therapy containing said complex as an active ingredient, and a process for their production.
BACKGROUND ART
Of radioactive transition metals used in radio-pharmaceuticals,
99m
Tc is a nuclide most often used in the field of radiopharmaceuticals for diagnostic imaging, and
186
Re and
188
Re are nuclides preferably used in the field of radiopharmaceuticals for therapy. Since these radioactive transition metals have different coordination numbers in different oxidized states and can form various complexes together with various ligands, they are used usually in the form of a complex. For example, as a process for producing the complex, there is a process of chelating ligands with Tc atom at first, and then attaching a physiologically active substance to the chelate, or a process of attaching a physiologically active substance to ligands at first, and then coordinating a Tc atom therewith. Whichever process is employed, it is usually difficult to carry out the above-mentioned attachment while maintaining the whole activity of the physiologically active substance. Such attachment is more difficult particularly in the case of a small compound.
There has recently been proposed a process comprising replacing a part of a physiologically active substance by a complex containing a metal ion, without impairing the activity of the substance (D. Y. Chi et al., J. Med. Chem. 1994, 37, 928-937). This process is advantageous in that a metal-containing block is accurately attached to the physiologically active substance, so that a structure very close to that of the original physiologically active substance can be maintained. However, no generally applicable process has yet been established.
Transition metal nitride complexes are excellent in stability to hydrolysis. Therefore, when a transition metal nitride complex is subjected to exchange reaction with any of various ligands having a useful physiological activity, when used in a pharmaceutical, the nitride group of the nitride complex can remain bonded strongly to the metal atom. Accordingly, transition metal nitride complexes having various substituents have been proposed. For example, WO 90/06137 discloses diethyl bisdithiocarbamate-Tc nitride complex, dimethyl bisdithiocarbamate-Tc nitride complex, di-n-propyl bisdithiocarbamate-Tc nitride complex, N-ethyl-N-(2-ethoxyethyl)bisdithiocarbamate-Tc nitride complex, etc.
In addition, WO 89/08657 discloses a process for producing a transition metal nitride complex which comprises reacting a phosphine-based ligand like a polyphosphine as a reducing agent for the transition metal with the transition metal oxide, then reacting a nitride of a metal or ammonium as a nitrogen source for nitride with the reaction product to convert it to the corresponding nitride, and then coordinating a physiologically active monoclonal antibody or the like with this nitride.
In these processes, the choice of the ligand having a physiological active group is so important that it determines properties of the resulting pharmaceutical. But, the metal nitride complex can have various numbers of coordination positions from mono-dentate to quadridentate and hence is formed in plural forms. Therefore, it has been difficult to obtain a single complex stoichiometrically having a specific physiologically active ligand.
DISCLOSURE OF INVENTION
When the radioactive metal is technetium or rhenium, oxidation number ranges between valency of +I and +VII. The oxidation number of nitride complex is generally the valency of +V, the metal atom thereof has five coordination positions and is expected to have a steric molecular configuration represented by the following formula (V) or formula (VI):
The geometry of the formula (V) is referred to as “square pyramidal geometry (sp geometry)”, and the geometry of the formula (VI) as “trigonal bipyramidal geometry (tbp geometry)”. In the above formulas, a, b, c, d, a′, b′, c′ and d′ are symbols affixed to coordination positions for convenience of explanation.
The sp geometry of the formula (V) is a square pyramidal geometry in which the coordination positions a, b, c and d form a square as a base and N is a vertex. It is considered that the tbp geometry of the formula (VI) is composed of the two trigonal pyramidal geometries which have a′ and d′ as the respective vertexes and have a triangle formed by b′, c′ and N on the same plane as a common base.
The present inventors earnestly investigated a combination of ligands capable of forming a complex of a single structure, among ligands which are likely to be coordinated with a transition metal nitride, for example, bidentate ligands, tridentate ligands and quadridentate ligands, and a process for forming such a complex, and consequently found that a single and stable transition metal nitride can be obtained by coordinating different two bidentate ligands unsymmetrically. Thus, the present invention has been accomplished.
The present invention is intended to provide a novel single radioactive transition metal nitride heterocomplex which permits labeling of physiologically active substances such as peptides, hormones, etc. without impairing their activity.
The present invention is a radioactive transition metal nitride heterocomplex comprising a radioactive transition metal nitride and two different ligands coordinated therewith which is represented by the following formula (I):
(M≡N)XY (I)
wherein a radioactive transition metal M is radioactive technetium or radioactive rhenium, N is a nitrogen atom, X is a diphosphine compound or a diarsine compound, and Y is a bidentate ligand having a combination of two electron-donating atoms which are selected from the group consisting of O, S and N and may be either charged or not.
Another aspect of the present invention is a process for producing a radioactive transition metal nitride heterocomplex according to claim
1
, which comprises a first step of reacting an oxide of a radioactive active transition metal M with either carbazic acid or its derivative, or hydrazine or its derivative, and a diphosphine compound or a diarsine compound in a solution in the presence or absence of a reducing agent, to obtain an intermediate of radioactive transition metal nitride; and a second step of reacting said intermediate with a bidentate ligand having a combination of two electron-donating atoms selected from the group consisting of O, S and N.
By the process for producing a novel radoactive transition metal nitride heterocomplex of the present invention, a single radioactive transition metal nitride heterocomplex can be obtained in high yield without producing an optical isomer, etc. Said complex is a novel complex composed of a core of a transition metal nitride, a diphosphine compound as a neutral bidentate ligand, and an electron-donating bidentate ligand, and the physiological activity of the electron-donating bidentate ligand itself or the molecular structure of a physiologically active species attached thereto is hardly impaired. Thus, the present invention has made it possible to obtain a radiopharmaceutical having a strictly controlled molecular structure.
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patent: 4916214 (1990-04-01), Chiu et al.
patent: 5300278 (1994-04-01), Pasqualini et al.
patent: 5399339 (1995-03-01), Pasqualini et al.
patent: 5496929 (1996-03-01), Pasqualini et al.
patent: 5-508842 (1993-12-01), None
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Bolzati Cristina
Duatti Adriano
Refosco Fiorenzo
Tisato Francesco
Uccelli Licia
Hartley Michael G.
Nihon Medi+Physics Co., Ltd.
Sughrue Mion Zinn Macpeak & Seas, PLLC
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