WO1998056427A1 - Novel contrast media - Google Patents

Abstract

A contrast medium which has high safety, can provide a high MRI signal intensity by virtue of a high level of restriction of the intramolecular rotational motion, and excellent handleability at the time of use by virtue of low viscosity; a metal cation complex which can stably disperse metal cations in a high concentration in an organic polymer material, a solvent, or a blood stream; and a contrast medium containing the complex as the indispensable component.

Description

 Description New contrast agents Technical field

 The present invention relates to a contrast agent comprising a metal cation and a ligand having a hyperbranched molecular structure. The contrast agent of the present invention provides a means for stably dispersing a metal element in a blood stream at a molecular level, and is suitably used in an X-ray contrast technique or a contrast technique utilizing a nuclear magnetic resonance phenomenon. . Since the contrast agent of the present invention uses a ligand having a hyperbranched molecular structure, the thermal motility of the complex, particularly the rotational motility, is significantly suppressed as compared with the conventional complex, and it is particularly suitable for MRI technology. It is a contrast agent.

 The present invention also relates to a metal cation complex comprising a branched polymer having a polyaminocarboxylate anion having a tertiary amino group and a carboxyl group, which are a group forming a functional group with a metal cation. This complex can be used not only as a contrast agent as described above, but also as a polymer composition that can be used in various other fields. Background art

 X-ray contrast technology (hereinafter abbreviated as XRI technology) is a technology that obtains an image by injecting an element with high X-ray absorption capacity and a high atomic number into a living body by some method, and then performing X-ray irradiation. Imaging technology (hereinafter abbreviated as MRI technology) using the nuclear magnetic resonance phenomenon (hereinafter abbreviated as NMR phenomenon) is a paramagnetic species (usually a gadolinium cation or other paramagnetic transition element cation) that causes an NMR phenomenon. ) Is injected into the living body by some method, and then an image is obtained by applying a magnetic field.In each case, in order to perform good imaging at a specific examination site, it is necessary to use A technique for stably dispersing the imaging chemical species in the aqueous solution for the decomposition is essential.

Early XRI techniques used a method of injecting the salt of iodide ion (I) into the blood, but there were problems with shock, pain, or thyroid disorders in the patients who received it. Was. To alleviate these serious side effects, Nonionic iodine compounds, for example, organic compounds containing a high concentration of iodine atoms, which have been rendered hydrophilic, are now widely used. However, even with such organic iodine compounds, side effects considered to be caused by iodine have been reported, and development of a new XRI contrast agent is desired.

 In MRI technology, trivalent gadolinium cation (Gd

Various methods have been proposed for dispersing ³⁺ ) stably in the bloodstream. For example, polyaminocarboxylic acids such as ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), or 1,4,7,10-tetrakis (acetic acid) tetraazacyclododecane (DOTA) are used. Complexes as ligands have been put to practical use. In such a complex, three carboxyl groups become carboxylate anions (COO) in order to neutralize the trivalent positive charge of the cation, and the oxygen atom of the remaining carboxyl group in the ligand and the nitrogen atom of the amino group It has a structure in which atoms are coordinated to the remaining coordination sites of the cation, but the stability of the complex is not sufficient, and side effects such as the release of the released cation from the bloodstream and deposition on bone are known. ing. Although the chemical properties of lanthanides such as gadolinium are generally similar to those of alkaline earth elements such as magnesium and calcium, their toxicity and safety have not been fully understood. However, suppressing the release of Gd3 ⁺ in blood is an important issue in MRI technology.

On the other hand, as one factor governing the contrast effect in MRI technology, for example, Toth, E. et al .; Chem. Eur. J., Vol. 2, No. 12, pp. 1607 (1996) As described in detail, it is the Rotational correlation relation time (abbreviated as r _R ) of the It body. This is qualitatively a measure of the rotational mobility of the complex, and it is desirable that this is large, that is, that the complex be difficult to freely rotate. As described in the above literature, it has been proposed to bind a polymer to a ligand as a means for increasing the _R value, and dendrimer is exemplified as a particularly effective polymer.

Dendrimers are described, for example, in Hawker, CJ eta 1; J. Chem. Soc., Chem. Commun., 1990, p. 1 ia, DA eta 1; Age w. Chem. Int. Ed. Enl., Vol. 29, pp. 13 (1990), Frechet, JMJ; Science, 26 Vol. 3, pp. 1710 (1994), or Masaaki Kakimoto; Chemistry, Vol. 50, pp. 608 (1995). Since such a molecule has a high molecular structure that is regularly branched from the center of the molecule, for example, as described in the above-mentioned literature by Tom a1ia et al. Due to the extreme steric crowding of the branched ends that occurs as the molecular weight increases, a spherical molecular form is obtained.

According to the above-mentioned publication by Toth et al., Since dendrimers have a highly controlled dendritic branch structure, the degree of freedom of the polymer chains to rotate in the molecule is higher than that of the linear polymer chains. Is extremely preferable to increase the τ R value. However, the complex described in this document has 1,4,7,10-tetrakis (acetic acid) tetraazacyclododecane (DOTΑ) at the end of the polymer chain of the dendrimer (ie, the surface of the spherical molecule). Omitted) and so on. Since it is a polycomplex having a ligand composed of a number of known polyaminocarboxylic acid structures such as, etc., any one polyaminocarboxylic acid structure coordinated to one Gd3 ⁺ which is a complex unit It is connected to the dendrimer in one place. For this reason, since the complex unit is free to rotate along the polymer chain axis at one end of each dendrimer, the rotational motility is not completely suppressed. In addition, since the complex unit is exposed on the surface of one molecule of the dendrimer, there is a concern that the complex unit has the same Gd ³⁺ release property as a low-molecular-weight complex that has been put into practical use. Furthermore, since the dendrimer surface the complex units are concentrated in some cases to reduce the signal strength T ₂ shortening effect comes out strongly in the MR I technology.

On the other hand, metal cations have various functions such as excitation by absorption of electromagnetic wave energy and fluorescence phenomenon by emission, emission of X-rays by electron beam irradiation, magnetism, various catalytic actions, and redox action. In order to make this function practical, it is necessary to control its state (eg, oxidation number, external environment such as ligands, dispersion state of individual atoms, etc.), or to form into a specific product form It is necessary to provide sex. The usual method for this purpose is to disperse the cation in a matrix material. is there.

 For example, when utilizing the electromagnetic functions of metal cations, such as fluorescence, the property of changing the speed of light passing through a matrix (that is, the change in refractive index), and the ability to absorb electromagnetic waves (especially X-rays) It is usually necessary that the matrix material used is sufficiently transparent in the desired electromagnetic wave wavelength range. For example, in technologies utilizing wavelengths in the visible light region, inorganic glass such as silicon glass has been an important matrix material in the past. This is due not only to the excellent light transmittance of the inorganic glass in a wide wavelength range, but also to the properties such as heat resistance, chemical resistance, water resistance, surface hardness, abrasion resistance, and low coefficient of linear expansion.

 As a technique for dispersing cationic metals, especially lanthanide cations having fluorescence, in an inorganic matrix, a method of melting and mixing at a temperature higher than the melting point, dissolving raw materials in an acid, etc., mixing them, then neutralizing and precipitating So-called coprecipitation method, solid-phase reaction method in which the raw material powder is mixed with the target composition and then heated at a high temperature to interdiffuse the ions, a method of injecting the element in the gas phase, and driving the element accelerated at high speed A so-called sol-gel method of hydrolyzing and condensing an alkoxide or the like of the element with an alkoxide or the like serving as a precursor of an inorganic matrix has been conventionally performed. In some cases, these elements can be mixed in the inorganic matrix to a concentration of about several percent by weight, but generally, the cation has low solubility in the inorganic matrix, or Since it was difficult to control the chemical structure near the cation, it had the disadvantage that it easily formed an aggregated state (cluster). In particular, in the case of utilizing the fluorescence of the cation, there is a drawback that the fluorescence intensity is rather lowered when the added concentration is increased to a certain level due to concentration quenching caused by the transfer of the excitation energy in the cluster.

On the other hand, advances in organic polymer material manufacturing technology have led to the development of transparent amorphous materials such as acrylic resins, styrene resins, aromatic polycarbonate resins, aromatic polyacrylate resins, polyimide resins, and amorphous polyolefin resins. Thermoplastic resin has been developed, and features that are not found in inorganic glass, such as excellent moldability such as thermoplasticity and solution applicability, light weight, toughness, versatility in the choice of monomer chemical structure, and compatibility with other materials Applications have been devised that take advantage of the characteristics such as adhesion and recyclability. For example, cameras and eyes Mirror lenses, automotive headlamp covers, transparent structural materials used in applications such as optical discs and compact discs, polymer materials for photoresists, or electrophotographic photoreceptors and binders for thermal transfer dyes The use of functional low molecular compounds as support media is expanding.

In view of the current state of such material technologies, for example, in the technical field such as optical communication technology, which has mainly been mainly composed of inorganic materials, or in the case of conventional inorganic substances such as phosphor technology or organic complexes having a relatively low molecular weight, these are mainly used. In the technical field, the development of new materials that make use of the specialty of organic polymer materials described above is one of the important tasks. More specifically, for example, an organic polymer fluorescent material having a high fluorescence generating ability, or a controlled refractive index, an amplification function for compensating for a loss (lower signal intensity) during optical signal transmission, and a wavelength. An organic polymer material having optical characteristics such as a conversion function is considered to be extremely useful. Examples of application of cations of fluorinated elements such as lanthanides to inorganic matrices include, for example, inorganic glasses to which cations such as elpium are added as materials for optical amplifiers in optical communication technology. Yes (Kimura et al., Op tr 0 nics, 1990, Issue 11, p. 47-53, Willi am J. Minisca 1 co; J. Ligh twa ve Te cn ology, 9, Vol., Pp. 234 (1991), and written as Emm anuel D esurvive; Erbium—Doped Fiber Amplifiers: Principles and Applications, John Wiley & Sons, New York rk (1994) etc.). This applies the excitation of erbium's f-orbital electrons with visible to near-infrared light (eg, at a wavelength of 980 nm) and the generation of fluorescence at a wavelength of about 150 nm. However, when inorganic glass is used as a matrix, the solubility of the erbium cation is relatively low, so that even at a few hundred ppm addition, cluster formation occurs due to association of the cation. As a result, since the concentration quenching becomes remarkable, there is a drawback that the fluorescence generation efficiency is conversely reduced even if added more, that is, the phenomenon of peaking of the light amplification function is observed. Also, because it is an inorganic glass material, its lightness, moldability, and toughness have not always been satisfactory. For the purpose of remedying these drawbacks, for example, Hoshino et al .; Proceedings of the Institute of Electronics, Information and Communication Engineers, 1991, 432, etc., use metal alkoxides and lanthanide chlorides as raw materials in homogeneous solutions. Discloses a method for obtaining a quartz film containing a rare earth element at a high concentration and uniformly by a hydrolysis condensation reaction in the above. In such a method, cracking and peeling of the quartz film from the substrate occur, so that there is a problem in forming processing such as difficulty in forming a thick quartz film on the substrate.

 On the other hand, the addition of lanthanide cations to organic polymer materials is also being studied. Examples are Ok amo to, Y. eta 1; Macromo lecules, Vol. 14, p. 17 (1980), and Heats, J. etal .; "Metal C ontaining Pollyme ric". Syst ems ", Plenum Press, New York (1995), and Yo shiyuki Ok a mo to; Proceedings of the Society of Polymer Science, Japan, 1994, 43 (1), pp. 29 For example, a lanthanide salt of a polymerizable organic acid such as acrylic acid, methacrylic acid, styrene carboxylic acid, and styrene sulfonic acid is synthesized, and the lanthanide cation-supporting monomer is polymerized or copolymerized. A method for increasing the ion concentration to about 10% by weight has been reported. Japanese Patent Application Laid-Open No. 5-86189 discloses a polysiloxane obtained by using chlorosilanes having an organic group and a chloride of a rare earth element as raw materials and having a lanthanide incorporated in a polymer chain. Have been. Further, JP-A-5-88026 discloses that a polyacrylate / polysiloxane contains a complex having excellent solubility and oxidation resistance in an organic solvent such as an acetylacetone complex of lanthanide. Material is disclosed.

 Although these methods are certainly effective in increasing the concentration of metal cations in the organic polymer material and give a material having apparently good transparency, the structure near the cation is precisely formed. The problem of concentration quenching is completely resolved because the cations are not controlled and the cations can still be associated at structural levels smaller than the wavelength of light, even if apparent transparency is achieved. Had not been.

On the other hand, inorganic phosphors commonly used in cathode ray tubes, fluorescent lamps, X-ray intensifying screens, and the like include multi-step processes that are complicated in their production, such as mixing, precipitation, filtration, and drying. The steps such as drying, baking, pulverization, and classification are usually required, and the dispersibility in the solvent or binder polymer when applying this to the base material may be insufficient, and as described above There were drawbacks such as concentration quenching due to the formation of clusters in the fluorescent species Lan-Yun Node. In addition, a lanthanide complex using a low-molecular organic ligand such as an acetyl acetonate derivative has been used as a fluorescent labeling agent such as a fluorophore for a fluorescent substance. After all, improvement of the fluorescence intensity, etc. was desired.

An object of the present invention is to provide a highly safe XRI contrast agent which can contain a metal element having a desired large atomic number in the form of a cation without using iodine having side effects, and has been suppressed. An object of the present invention is to provide a contrast agent for MRI which has a large _R value due to its cation releasing property and extremely suppressed rotational motility, and which is excellent in safety and performance.

 Another object of the present invention is that when metal cations are dispersed at a high concentration in an organic polymer material or a solvent, the formation of clusters can be extremely suppressed, and an element having a high atomic number can be suppressed. An object of the present invention is to provide a metal cation complex that provides a means for dispersing cations stably in a blood stream. Disclosure of the invention

In order to solve the above-mentioned problems, the present inventor has conducted intensive systematic research, particularly on the complexation of a metal cation and an organic material, and has found that a coordination containing a hyperbranched molecular structure in a specific bonding mode It has been found that complexing a proton with a metal ion is very effective. In other words, in such a complex, the metal cation is not exposed on the surface of the dendrimer, and the hyperbranched molecular structure arranged in the vicinity of the metal cation has a large space exclusion effect (effect of occupying a large space). It is thought that the stability in blood is improved due to the fact that the complex is functionally shielded from the metal cation. It has been found that the compound has a very large _R value as described above, and that a strong MRI signal intensity can be obtained, and has completed the present invention. In order to solve the above-mentioned problems, the present inventor has conducted intensive systematic studies especially on the composite of a metal cation and an organic polymer material. By forming a complex in which a branched polymer having a polyaminocarboxylate anion having a tertiary amino group and a carboxyl group, which are a complex-forming functional group, is arranged near a metal cation by bonding, the cation is converted to a complex. It has been found that the complex can be solubilized stably in a wide range of solvents and the obtained complex can be made thermoplastic. In addition, such complexes maintain the characteristics of the branched polymer, such as reduced weight, toughness against bending displacement, or adhesion to a wide variety of substrates. Further, the cations are not exposed on the surface of the dendrimer, and are aggregated with each other in principle due to the large space exclusion effect (the effect of occupying a large space) of the branched polymer arranged near the metal cation. Due to the difficulty, when this is dispersed in various matrices, the cations are dispersed at the atomic level, which extremely suppresses the formation of clusters and also suppresses the decomposition of complexes due to ion exchange in the aqueous electrolyte solution. And found that the present invention was completed.

That is, the gist of the present invention is a complex comprising a metal cation and a ligand having a hyperbranched molecular structure, and wherein a complex-forming functional group in the ligand is located between a focal point atom of the hyperbranched molecular structure. A contrast agent comprising, as an essential component, a complex which is not a constituent element of the hyperbranched molecular structure and is bonded through 0 or more and 50 or less atoms bonded in series; wherein the ligand is a water-soluble contrast agent; The above-described contrast agent wherein the ligand has an active hydrogen atom-containing functional group or a polyalkylene oxide group at the terminal of the hyperbranched molecular structure; the ligand is a hydroxyl group or a polyalkylene oxide group having a repeating unit of 4 or less carbon atoms. Wherein the ligand comprises an element arbitrarily selected from the group consisting of oxygen, nitrogen, sulfur, and phosphorus in the hyperbranched molecular structure; The child is Aete The contrast agent having a structure arbitrarily selected from the group consisting of, an ester, an amide, and a tertiary amamine in the hyperbranched molecular structure; the contrast agent having a ligand having a porphyrin ring; The contrast agent having a molecular structure of not less than 300 and not more than 500, 000 or less; the contrast agent having a hyperbranched molecular structure having a dendrimer structure; and the focal point atom having a hyperbranched molecular structure having a On average for one metal cation The contrast agent wherein the metal cation is a cation of an element belonging to the sixth period of the periodic table; and the contrast agent wherein the metal cation is a trivalent cation. The contrast agent wherein the metal cation is a cation of gold or platinum; the metal cation is a group 3A, 4A, 5A, 6A, 7A, 8A, or 8A of the periodic table; The contrast agent which is a cation of a transition metal belonging to any one of the groups 1B and 2B and has paramagnetism; the metal cation is manganese, iron, or lanthanide The contrast agent, wherein the metal cation is a trivalent gadolinium cation; or the contrast agent, wherein the complex is represented by the following general formula (1);

M ^{n +} (RA)…… (1)

(In the above formula, ^{π π +} represents an n-valent metal cation, RA— represents a monovalent acid anion, n is an integer of 1 to 4, R represents a hyperbranched molecular structure, and A Represents a carboxylate group or a sulfonate group which is a complex-forming functional group.)

 The contrast agent, wherein the complex is a metal cation complex represented by the following general formula (2);

M ^{n +} (X ⁿ ) — R _m … (2)

(In the above formula, M ^{n +} represents an n-valent metal cation, (X ⁿ —) — R _m represents a ligand, and X represents a tertiary amino group and a carboxyl group which are complex forming functional groups. the represents an n-valent carboxylate anions of Poria Minokarubon acids having, R _m represents a good branched polymer residues be different Rusorezore independent each other to bind to X ^n, n is an integer of 1 to 4 And m represents an integer of 1 to 6. The branched polymer residue R is a number average molecular weight Mn, GPc, and a weight average molecular weight Mw ( _GPC ) measured by gel permeation chromatography ( _GPC ). Between the two, 300 0 ≤ Mn ( _GPC) ≤ 500 000 and 1.0 Mw (the two relations of ope, / Mn, _G pc, ≤ 15 are simultaneously satisfied.)

Ligand (X) —the branched polymer residue in the ligand (X ⁿ —) -R _m wherein at least one of the branched polymer residues R in R _m has a hyperbranched molecular structure; At least one of R is the true weight average molecular weight Mw measured by mass spectrometry or light scattering method and the weight average molecular weight measured by gel permeation chromatography (GPC) method. Contrast agent satisfying the relationship of Mw ( _GPC > with MwZMw ( _GPC) >1; ligand (Χ ^π ) — at least one of the branched polymer residues R in R _m is de Ndorima - the contrast agent is, ligand (chi ^[pi -) - one even without less of branched polymer residues R in R _m, wherein the contrast agent composed of an aromatic ring-containing monomer units; metal A complex comprising a cation and a ligand having a hyperbranched molecular structure, and a complex-forming functional group in the ligand is located between the focal point atom of the hyperbranched molecular structure and a component of the hyperbranched molecular structure A complex bound through a series bond atom of 0 or more and 50 or less, and a pharmaceutical composition for in-vivo diagnosis comprising a pharmaceutically acceptable carrier; a metal cation represented by the general formula (2): Ion complex; a metal cation complex represented by the general formula (2) is a polymer matrix A polymer composition having a metal cation concentration of 0.01 to 10% by weight, the metal cation complex being represented by the following general formula (2): A molded body whose outer surface is formed of a polymer composition in which a metal cation complex represented by the general formula (2) is dispersed in a polymer matrix in an amount of 0.01 to 10% by weight; BEST MODE FOR CARRYING OUT THE INVENTION The present invention resides in a coating material containing a metal cation complex represented by the general formula (2).

 Hereinafter, the present invention will be described in detail.

 << 1. Contrast agent >>

 The contrast agent of the present invention will be described.

 (Complex)

 The complex for a contrast agent of the present invention comprises a metal cation described below and a ligand containing a hyperbranched molecular structure in a specific bonding mode as described below as constituent components, and a Coulomb force or a coordination bond between the two components. It consists of. The contrast agent of the present invention is preferably a water-soluble one or a hydrophilic one that does not cause precipitational aggregation in water. The means for imparting water solubility or hydrophilicity will be described later.

 (Metal cation)

In the present invention, the metal cation is defined as hydrogen, boron, carbon, Excluding nitrogen and phosphorus, 1 A (alkali metal), 2 A (alkaline earth metal), 3 A 4 A 5 A 6 A 7 A 8 1 B 2 B (above transition element), 3 B 4 B and 5 It is a cation of an element belonging to each group of B. The valence of the metal cation is not particularly limited, but the complex of the present invention may be arranged with a ligand containing a sterically crowded hyperbranched molecular structure in a specific bonding mode in the vicinity of the metal cation. In order to avoid excessive spatial crowding, 1 to 4 valences are usually preferable, and more preferably 2 or 3 valences, and most preferably 3 valences, in terms of the efficiency of the space elimination effect described above. I do. Specific cations used in the complex for contrast agent of the present invention include metal cations such as Li ⁺ Na ⁺ K ¹ Rb ⁺ , C s ⁺ F r ⁺ , and Be ^{2 +} Mg Alkaline earth metal cations such as ^{2 +} , C a ^{2 +} , S r ^{2 +} B a ^{2 +} , R a ² , scandium cations such as Sc ³⁺ Y ³⁺ , T i ² T i ³ T i ⁴⁺ Z r + Z r ²⁺ Z r ³ Z r ⁴⁺ H f ⁺ , Η f ²⁺ , Η f ^{;, +} , Η f ^4+, etc., V ⁺ V ²⁺ , V ³ V ⁴ V ^{B +} , Nb + Nb ²⁺ Nb ³⁺ Nb ⁴⁺ , Nb ^{5 +}

Vanadium-group cations such as T a Ta ² T a T a ⁴⁺ , T a ⁵⁺ , C r C r C r ³ C r ^h , C r ⁵⁺ C r ⁶ Mo + Mo ²⁺ , Mo ³⁺ Mo ⁴ Mo Mo ^e W ⁺ _; Chromium group cations such as W ²⁺ , w ⁴⁺ , ^{zu +} , W ⁶⁺ , etc., Mn Mn ^E Mn Mn ⁴⁺ Mn ⁵⁺ , Mn ^{6 +} Mn ⁷ 'Tc + T c Manganese family cations such as ^{2 +} T c T c ⁴ T c Tc ^{6 +} , T c ^{7 +} R e ⁺ , Re ² R e ³ 'R e ⁴ R e R e R e ^{7 +} , F e Fe ²¹ F e ³ F e F E ^f Ru, Ru ² Ru ³⁺ , Ru ⁴⁺ , Ru Ru ⁶ Ru ⁷ Ru 0 s 0 s ² 0 s ³⁺ 0 s ⁴ 0 s 0 s 0 s ⁷ 0 s ^{8 C0} Co ²⁺ Co ³ C o C o Rh ⁺ Rh ² Rh ³⁺ , Rh ⁴⁺ , Rh Rh ⁶⁺ , I r +1 r 1 r 1 r ⁴ 1 r ⁵

I r ^{6 +} like cobalt Group ^{cation, N i + N i 2 N} i E N i P d + P d 2+, P d 3+ P d 4+ P t 2+ P t 3 P t P t P nickel group cations such as ^{t 6+, C u C u 2} + C u 3 'C u 4 a g a g 2 +, a g 3 +

Copper group cations such as Au ⁺ Au ²⁺ Au ³⁺ Au ⁵⁺ , Au ⁷ , zinc group cations such as Zn ²⁺ Cd ⁺ Cd ²⁺ Hg Hg ²⁺ , La ²⁺ La ³ ′, Ce ² C e ^{3 C e 1+ P r 21 P r} 3 P r "Nd 2 + Nd 3+, N d 4+ Pm Pm 3 Sm 2 + Sm 3 Eu 2 + E u 3+ Gd 2 + Gd 3 Tb 2+ Tb Tb 4 ^{Dy 2 + Dy 3 Dy 4 +} Ho 2+ Ho 3 + E r 2+ E r 3 Tm Tm 3 'Yb 2 + Yb 3 Lu 2 + L u 3+ etc. lanthanoid de cations, Ac Th ^{4 +} P a ^{3 +} Pa ⁴ Pa ^{5 +} U ³⁺ U ⁴ UU ^{6 +} Np ³⁺ , N p 'N p ^{5 +} Np ^{6 +} Pu ³ Pu ^{4 +} Ρ υ ⁵⁺ Pu ⁶⁺ , Am ^{2 +} Am ³⁺ Am 'Am ^{5 +} Am ^{6 +} Cm ³ Cm ^{4 +} Β k ³⁺ Bk ⁴ C f ^{2 +} C f ³⁺ C f' E s ^{2 +} E s ^{3 +} Fm ² Fm ^{3 +} Md ²⁺ Md ³⁺ , No ² No ³⁺ etc. Akuchinoi de ^{cations, a 1 Ga 2 + G a} 3+ I n ', I n 2' I n 3 ^{bets, T 1 + T 1 2+ T} 1 3+ 3 B group such ^{cation, S i 2+ S i Ge 2} Ge 4+ S n 2+, Sn 4 P b 2, 4 B Zokuhi ions such as ^{P b 4, As As 5 S} b 1, S b 3+ S b " Group 5B cations such as B i, B i ³⁺ B i ^{5+ and the} like can be mentioned.

 For the purpose of increasing the X-ray absorption capacity of the complex for a contrast agent of the present invention, the higher the atomic number of the metal cation among the above cations, the more effective. Specific examples include cations of elements belonging to the fourth, fifth, sixth and seventh periods of the periodic table. However, from the viewpoint of its effect and economy, element Yon, which belongs to the 6th period, is preferred. More preferred are lanthanide cations such as thulium, ytterbium and lutetium, or noble metal cations such as gold and platinum, and most preferably gadolinium, gold or platinum.

When the complex for contrast agent of the present invention is used as a contrast agent for MRI, the cation needs to have paramagnetism. For such purposes, transitions that typically belong to any of the groups 3A, 4A, 5A, 6A, 7A, 8, 8, 1B, and 2B of the periodic table Use metal cations. The magnetism of the transition metal shows complex behavior depending on the oxidation number and the nature of the ligand.Pr ³⁺ Nd ³¹ , Eu ³⁺ , Gd ³⁺ Tb ³⁺ Trivalent lanthanide cations such as Dy ³⁺ Ho ³⁺ , Er ³⁺ Tm ³⁺ , Y b ³ , manganese group cations such as Mn ²⁺ Mn ³⁺ , iron groups such as F e ² F e ³ Cation, N i ^2+, Ni group cations such as the N i ^3+, and the like as a typical, among others ^{Gd 3 +, F e 2 +} , F e 3 +, Mn 2 + and the like are preferable, Most preferred is Gd ³⁺ .

 (Ligand)

 The ligand, which is a component of the complex for a contrast agent of the present invention and has a hyperbranched molecular structure in a specific bonding mode, is characterized in that the complex-forming functional group in the ligand is a focal point having a hyperbranched molecular structure. ) It must be bonded to the atom via 0 to 50 serially connected atoms that are not components of the hyperbranched molecular structure.

Here, the complex-forming functional group in the ligand is a functional group that interacts with the metal cation in the complex by Coulomb force or coordination bond. Examples of such a functional group include a hydroxyl group, a sulfonyl group, a phosphate group, a phosphite group, a hypophosphite group, a thioate group (—COSH), a dithioate group (—CSSH), a xanthate group, and a nitrate group. Hydroxy groups such as alcoholic hydroxyl group, phenolic hydroxyl group, etc., primary amino group, secondary amino group, tertiary amino group, nitro group, nitrile group (cyano group), isonitrile group, etc. Functional group, nitrogen-containing aromatic ring such as pyrrole ring and pyridine ring, sulfur-containing functional group such as mercapto group (thiol group), disulfide group, sulfide group, isothiocynate group, thiocarbamate group, phosphine group, Phosphorus atom functional groups such as phosphinoxide groups, selenium-containing functional groups such as selenol groups, diselenide groups and selenide groups, and anionic groups generated when the above acidic groups lose protons (A carboxylate group, a sulfonate group, a phosphonet group, a xanthate group, etc.), an anionic group (eg, an alcoholate group, a phenolate group, etc.) generated by losing a proton in the above hydroxyl group, a carbonyl group, an enolate group, etc. Can be illustrated. Of these, acid-forming groups such as carboxyl group, sulfonyl group, phosphate group, xanthate group, etc., and anionic groups (eg, those groups formed by losing protons) are preferable in terms of complexing ability and safety. A carboxylate group, a sulfonate group, a phosphonate group, a xanthate group), a nitrogen-containing functional group such as a primary amino group, a secondary amino group, a tertiary amino group, a nitrile group, a pyrrol ring, a pyridine ring, etc. Sulfur-containing functional groups such as nitrogen-containing aromatic ring, mercapto group, disulfide group, sulfide group, thiocarbamate group, phenolic hydroxyl group, phenol — Acid groups such as carboxyl group, sulfonyl group, etc., and anionic groups generated by losing protons (carboxylate group, sulfonate group, etc.) ), Nitrogen-containing functional groups such as tertiary amino groups and nitrile groups, nitrogen-containing aromatic rings such as pyrrolyl rings, sulfur-containing functional groups such as mercapto groups, disulfide groups, sulfide groups, thiocarbamate groups, and phenol. More preferred are a hydroxyl group, a carbonyl group, an enolate group, etc., and an acidic group such as a carboxyl group or a sulfonyl group, and an anionic group formed by losing a proton from these acidic groups (a carboxylate group, a sulfonate, respectively) Groups), a nitrogen-containing functional group such as a tertiary amino group, and a nitrogen-containing aromatic ring such as a pyrrol ring are most preferred.

 The complex-forming functional groups exemplified above may be present in any number and in any combination in one ligand, and a series of such functional groups form the coordination site of the metal cation. They are often arranged with the intent to occupy them efficiently and exhibit excellent complex stability. However, from the viewpoint of coordination efficiency to metal cations, the number of the functional groups present in one ligand is suitably 1 or more and 30 or less, preferably 1 or more and 20 or less, It is more preferably 1 or more and 15 or less, most preferably 1 or more and 10 or less. Further, the adjacent functional groups are desirably separated by 0 to 10 series-bonded atoms, and the number of the series-bonded atoms is more preferably 0 to 7 and still more preferably 0 to 5 Below, most preferably 0 or more and 3 or less. Examples of the structure of a series of the functional groups exhibiting excellent complex stability that can be used in the complex for a contrast agent of the present invention include ethylenediaminetetraacetic acid (commonly known as EDTA), diethylenetriaminepentaacetic acid (commonly known as DTPA), 4,7,10—Tetrakis (acetic acid) Represented by polyaminocarboxylic acids such as tetraazacyclododecane (DOTA), and porphyrins such as porphyrin ring, protoporphyrin ring, etyoborphyrin ring, and mesoborphyrin ring. And polynitrogen-containing aromatic rings.

The ligand which is a constituent of the complex for a contrast agent of the present invention has a hyperbranched (Hyperbranch) molecular structure. Here, the hyperbranched molecular structure is a dendritic branched molecular structure.For example, the hyperbranched molecular structure is a concept typified by the dendrimer described in detail in each of the above-mentioned Hawker, Tomalia, Frechet, or Kakimoto et al. There is There is no limitation on the molecular weight in the light. If the hyperbranched molecular structure in the present invention is more strictly defined, the starting point of branching (hereinafter referred to as “focal point”) can be specified, and when the molecular chain is traced from the focal point toward the molecular end. It has a molecular structure that has at least one molecular end that passes at least one branch point other than the focal point. In addition, the focal point in the present invention means the last branch point in the shortest route from the arbitrary molecular end of the ligand in the complex to the nearest complex-forming functional group by reversing the molecular chain.

 The complex-forming functional group in the ligand, which is a component of the complex for a contrast agent of the present invention, is not a component of the hyperbranched molecular structure between the focal point atom of the hyperbranched molecular structure and 0 or more and 50 or less. Must be connected through the atoms connected in series. The term “sequentially bonded atoms” as used herein means a linear structure, and its constituent elements are not limited. However, when the contrast agent complex of the present invention is used as an MRI contrast agent, the vicinity of the central cation is hydrophilic. In some cases, it is preferable to include elements such as oxygen, nitrogen, and sulfur in the linear structure because it is desirable to have a natural environment. By controlling the number of atoms or the kind of elements connected in series, it is thought that the spatial or chemical environment near the metal cations can be changed. Specifically, for example, with the MRI contrast agent in mind When placed, it can control the accessibility of water molecules to paramagnetic metal cations, which greatly affects its performance. If the number of the atoms bonded in series is 50 or more, the shielding effect of the hyperbranched molecular structure in the ligand may decrease, which is not preferable. More preferably, the number is 40 or less, Preferably it is 30 or less, most preferably 25 or less. The ligand which is a component of the complex for a contrast agent of the present invention preferably has hydrophilicity or water solubility. Here, “hydrophilic” means that the complex does not cause precipitable aggregation in water, and “water-soluble” means that the complex dissolves in water without forming an aggregated structure. Even when the complex is not hydrophilic or water-soluble, it may be possible to administer the complex as a contrast agent to a patient in a state of suspension in water or an aqueous solution. It cannot be said that it is preferable because the contrast effect is lowered.

As a method for imparting hydrophilicity or water solubility to the ligand, an active hydrogen atom-containing functional group or a polyalkylene oxide group is introduced into the terminal of the hyperbranched molecular structure of the ligand. Method is suitably used. This is because such terminals exist on the surface of the complex. Examples of the active hydrogen atom-containing functional group include a hydroxyl group, a mercapto group, an amino group, a hydrazide group, a carboxyl group, a sulfonic acid group, an amide group, a carbamate group, a urea group, a thioic acid group and a dithioic acid group. Among them, a hydroxyl group, an amino group, and a urea group are particularly preferable. Preferable examples of the polyalkylene oxide group include a polyethylenoxide group, a polypropylene oxide group, a polybutylene oxide group, a polypentylene oxide group, a polyhexylene oxide group, a polyisopropylene oxide group, and a polyisopropylene oxide group. A monomer unit structure having an alkylene group having 6 or less carbon atoms in the repeating unit such as an isobutylene oxide group, a polycyclopentylene oxide group, and a polycyclohexylene oxide group may be mentioned. The above may be copolymerized. Of these, a hydroxyl group, a urea group, and a polyalkylene oxide group having a repeating unit of 4 or less such as a polyethylene oxide group, a polypropylene oxide group, and a polybutylene oxide group are most preferable. Preferred are a hydroxyl group and a polyethylene oxide group. In addition, functional groups having no active hydrogen atom, such as carbonyl group, ester group, nitrile group, nitro group and aldehyde group, are also effective for imparting hydrophilicity. As long as the hydrophilicity and water-solubility of the contrast agent complex of the present invention are not impaired, a ligand having two or more of the above functional groups in a molecule may be used as a component thereof. May be used in combination.

As another method for imparting hydrophilicity or water solubility to the ligand, a hyperbranched molecular structure in the ligand contains an element arbitrarily selected from the group consisting of oxygen, nitrogen, sulfur, and phosphorus. At least, a method for imparting water solubility to the hyperbranched molecular structure itself is given. Specific examples of such a structure include an oxygen-containing structure such as an ether bond, a carbonyl group, an ester bond, a carbonate bond, a furan ring, an amide bond, a urethane bond, a urea bond, and a secondary or tertiary amine structure. Non-aromatic nitrogen-containing structure, pyrrole ring, pyridine ring, quinoline ring, pyrimidine ring, purine ring, imidazole ring, imidazolidinine ring, triazole ring, etc., nitrogen-containing aromatic ring, sulfide bond , Disulfide bond, thiocarbonyl group, thioester bond, thiocarbonate bond Non-aromatic sulfur-containing structures such as thiourethane bond and thiourea bond, sulfur-containing aromatic rings such as thiazole ring, thiophene ring, and thionaphthene ring, phosphate ester, phosphite ester, hypophosphite ester, Examples thereof include a phosphorus-containing structure such as a secondary or tertiary phosphine and a phosphinoxide. Of these, oxygen-containing structures such as ether bonds, carbonyl groups, and ester bonds; amide bonds; non-aromatic nitrogen-containing structures such as tertiary amine structures; nitrogen-containing aromatic rings such as pyridine rings; and non-aromatic nitrogen-containing structures such as sulfide bonds. Aromatic sulfur-containing structures, phosphorus-containing structures such as tertiary phosphines and phosphinoxides are preferred, and non-aromatic nitrogens such as oxygen-containing structures such as ether bonds and ester bonds, amide bonds and tertiary amine structures. The containing structure is most preferred.

With high-molecular structure having a 3 0 0 or 5 0, 0 0 0 The following molecular weight as the hyperbranched molecule structure, to shield the metal cations effect a complex of Ro tati 0 na 1 correlationti me (Te _R) (Refer to the above-mentioned Toth et al. Document). If the molecular weight is less than 300, the effect of using the polymer is hardly obtained, while if it exceeds 50,000, the complex becomes too large and excretion from the body is extremely deteriorated. Therefore, the range of the molecular weight is preferably from 300 to 400,000 or less, more preferably from 400 to 300,000 or less, and still more preferably from 450 to 200,000. 0 or less, most preferably 500 or more and 100 or less. When such a high molecular weight hyperbranched molecular structure is used, its molecular weight distribution is different from the number average molecular weight Mn ( _GPC ) and the weight average molecular weight Mw ( _GPC) measured by the gel permeation chromatography (GPC) method. ≤Mw _<GPC) / Mn, it is desirable to satisfy the _G Pc, 1 5 the relationship. If the value of Mw ( _GPC) / Mn (GPc, above ₎ exceeds 15, the spatial spread of the complex becomes too large and the shielding effect may be impaired. Therefore, Mw ( _CPC ) It can be said that the smaller the value of / Mn,, the better, but it is more preferably 1.0 or more and 12 or less, more preferably 1.0 or more and 9 or less, and most preferably 1.0 or more and 5 or less. , as accompanying effect of using the polymer as hyperbranched molecular structure, since each metal cation Ion hardly close to each other, MR I signal intensity sidelines strongly T ₂ shortening effect even when used in high concentrations as a contrast agent Anticipated to keep the decline Is done.

 It is desirable that the above-mentioned hyperbranched molecular structure has as high a degree of branching as possible, particularly when the molecular weight is increased. This is thought to be because when considering molecules having the same molecular weight in the same monomer (repeating unit) structure, the larger the number of branch points, the easier it is to adopt a conformation with a high space exclusion effect. In other words, as it approaches a linear macromolecule without branching, it can change from a thread-condensed conformation with a high space exclusion effect to a low-conformation conformation with a stretched polymer chain. As a result, the probability of taking a state where the space exclusion effect is low increases. Means for quantifying the degree of branching of a polymer include, for example, measurement of the relationship between the intrinsic viscosity and the absolute molecular weight in a dilute solution, or the structure of a branched unit and an unbranched unit in a nuclear magnetic resonance (NMR) spectrum. A method utilizing the integral value of a signal assigned to each of the structures may be mentioned. In the present invention, when the molecular weight of the hyperbranched molecular structure exceeds 2,000, preferred conditions for the degree of branching include: For example, the weight average molecular weight Mw measured by the mass spectrum method or the light scattering method and the weight average molecular weight Mw measured by the GPC method satisfy the relationship of Mw / Mw, GPc,> 1. Can be

Examples in which Mw is larger than Mw ( _GPC) are described in Hawker, CJeta 1 J. Am. Chem. Soc., Vol. 112, pp. 7638 (1990) and Uh rich , KE etal; Macromo lecules, Vol. 25, p. 4583 (1992), etc., which are absolute as measured by the mass spectral method or the light scattering method. Even if the molecular weight (ie, Mw) is the same, as the degree of branching increases, the spatial extent of the polymer chains observed in a good solvent (ie, Mw ( _GPC) ) qualitatively decreases with decreasing size. Has been interpreted. The above-mentioned mass spectral method is not limited as long as a molecular peak is given, and is suitably used for relatively high molecular weight molecules having a molecular weight of 100 or more or unstable molecules. In some cases, it may be preferable to apply a new method such as the Matrix Assisted Laser Des- ptionionization (MALD I) mass spectrometer or the Electrospray mass spectrum. Also, all GPC measurements in the description of the present invention need to be performed in a good solvent having a hyperbranched molecular structure. MwZ The value of Mw (ope,) is usually at most about 3 within the above-mentioned range of molecular weight, but is not particularly limited.

The most effective hyperbranched molecular structure in terms of the effect of shielding the metal cation and the effect of increasing the _R of the complex is the above-described dendrimer structure. It is presumed that this is mainly due to the effective effect of eliminating the space and the two effects of extremely reducing the free rotation inside the structure due to the regular and dense branch structure of the dendrimer. In the case of dendrimers, it is theoretically also advantageous that the molecular weight distribution can be set to 1.0 with the value of Mw ( _GPC) / Mn ₍ Gpc, ₎ .

 It is preferable that two or more hyperbranched molecular structural units in one complex are contained as an average of two or more four-force point atoms in the hyperbranched molecular structure with respect to one metal cation. This is thought to be the effect of multiple independent hyperbranched molecular structural units significantly reducing the free rotation of metal cations. From the viewpoint of this effect, it is most preferable that the number of hyperbranched molecular structural units is three or more on average for one metal cation as the number of focal point atoms.

 (Method for producing complex)

 The complex for a contrast agent of the present invention comprises a cron force (ionic bond) or a coordinate bond between a metal cation and a complex-forming functional group in a ligand. The formation of ionic bonds is possible by an anion exchange reaction. More specifically, a salt of a metal cation with a carboxylic acid such as formic acid, acetic acid, oxalic acid, or propionic acid, or a salt with a chloride ion, a bromide ion, or an iodide ion, and a ligand or It is carried out by mixing with a salt of a ligand (for example, sodium salt, potassium salt, etc.).

In the complex for a contrast agent of the present invention, it is preferable that all the counter ions which neutralize the positive charge of the metal ion are the above-mentioned ligands. This is because relatively small anions, such as fluoride ions, chloride ions, bromide ions, halide ions such as iodide ions, sulfate ions, nitrate ions, formate ions, acetate ions, oxalate ions, etc. This is because the residual Yin, which is widely used in the field, reduces the shielding effect and the free rotation suppression effect. Therefore, when the complex of the present invention is produced by the above-described anion exchange reaction, the equivalent relation between the metal cation and the ligand is accurately controlled. Is desired. However, the effect of the present invention may be obtained even if an excess of a ligand is allowed to act on the metal cation because the product contains the desired complex.

 (Contrast agent)

 Further, the complex of the present invention is used as a contrast agent. In this case, parenteral administration such as intravenous administration or the like can be used. Solvents or suspending agents used in the preparation of parenteral drugs, that is, in the manufacture of injections, etc., include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, etc. No. Preparation of the preparation may be performed according to a conventional method. For oral administration, alone or in combination with a pharmaceutically acceptable carrier, for example, granules, fine granules, powders, tablets, hard syrups, soft capsules, syrups, emulsions, suspensions, Oral administration in the form of ribosomes, liquids, etc. Examples of excipients used in producing a solid preparation include lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. Liquid preparations for oral administration, ie, emulsions, syrups, suspensions, solutions and the like, contain commonly used inert diluents such as vegetable oils. The formulation may also contain, in addition to the inert diluent, an auxiliary such as a wetting agent, a suspending aid, a sweetening agent, a fragrance, a coloring agent or a preservative. Liquid preparations may be included in the forceps of a resorbable substance, such as gelatin.

 The contrast agent according to the present invention is generally administered at a dose that allows the desired contrast effect to be obtained without side effects. Its specific value is to be determined at the discretion of a physician, generally 0.1 mg to 10 g, preferably 1 mg to 5 g per adult per diagnosis. The compound of the present invention may be contained and administered as an active ingredient in an amount of 1 mg to 5 g, more preferably 3 mg to 3 g, per adult per diagnosis. << 2. — Metal cation complex represented by general formula (2) >>

 The metal cation complex represented by the general formula (2) of the present invention will be described.

(Metal cation complex)

A preferred metal cation complex of the present invention is represented by the general formula (2), and will be described later. The metal cation M ^{n +} and a branched polymer having a polyaminocarboxylate anion having a tertiary amino group and a carboxyl group, which are complex-forming functional groups, are constituent components, and electrostatic interaction between both components is performed. It is constituted by an action or a coordination bond. This metal cation complex is a force that binds a lipoxylate anion (COO—) of a number equal to the valence n of the metal cation to become electrically neutral. A form in which a part of the carboxylate ion is replaced with a small ion such as a hydroxide ion is also possible.

 (Metal cation)

In the general formula (2), the metal cation represented by M ^{n +} is the same as described above.

Among them, Pr ³⁺ , N d ³⁺ , Sm ³⁺ , Eu ³⁺ , Tb ³⁺ , D y ^{3 +} , Ho:! ⁺ , Er ³⁺ , Tm ³⁺ , Yb ³⁺ trivalent lanthanoid de cations etc., visible to near infrared region, a long life, are preferred in that fluoresces with a characteristic, such as a narrow wavelength ^{width, H o 3+, E r 3} +, Tm 3 + in etc. upconverter job Nreza first material, £ 11 ² tens Ya Ding 13 ³⁺ to visible light isolator using a rotary ^{F araday, P r 3+, Sm} 2 +, E u 3+ , etc. ho one These elements are useful elements for optical information recording materials utilizing the levering phenomenon. ^{P t 2+, P t 3+,} Au +, Au 2+, Au 3+, P b 21, B i 3 ten atomic number high cation increase the refractive index, such as electromagnetic wave absorbing effect, such as X-ray or, electromagnetic wave is suitable in terms of shielding ^{effect, L i +, Na +,} Κ ', Rb +, C s + etc. § alkali metal ^{cation, Mg 2+, C a 2+,} S r 2+, B Alkaline earth metal cations such as a ²⁺ are preferred in terms of antistatic effect.

 (Ligand)

(X) — In the ligand represented by the general formula of R _m , X ⁿ — is a tertiary amino group, which is a complex-forming functional group that electrically neutralizes the n-valent positive charge of the metal cation. And an n-valent carboxylate anion of a polyaminocarboxylic acid having a carboxyl group, and R represents a branched polymer residue. The term “branched polymer residue” as used herein means a polymer structure having a branch in the main chain structure. Here, n represents an integer of 1 to 4.

Polyamides containing tertiary amino groups and carboxyl groups, which are the above complex forming functional groups N-valent carboxylate anions X ⁿ of Nokarubon acid - A represents a straight-chain or cyclic compounds having at least one tertiary Amino groups and two or more carboxyl groups, a series of these functional groups is a metal cation It is arranged with the intention of efficiently occupying the coordination site. However, from the viewpoint of the coordination efficiency to the metal cation, the total number of the tertiary amino group and the carboxyl group present in one X is suitably 30 or less, preferably 20 or less. The value is more preferably 15 or less, most preferably 10 or less. The adjacent functional groups are desirably separated from each other by 0 to 10 series-bonded atoms, and the number of the series-bonded atoms is more preferably 0 to 7 but still more preferably 0 or more. 5 or less, most preferably 0 or more and 3 or less. Examples of such a structure include ethylenediamine tetraacetic acid (commonly known as EDTA), methylentriamine pentaacetic acid (commonly known as DTPA), or 1,4,7,10-tetrakis (acetate quat) tetraazacyclododecane (commonly known as D0 TA)) and the like.

 The chemical structure of the monomer constituting the branched polymer residue is not particularly limited as long as both the solvent solubility and the thermoplastic property of the metal cation complex represented by the general formula (2) are not impaired at the same time. There is no. This is because, in the present invention, one of the main reasons for using branched polymer residues is due to its spatial exclusion effect. That is, regarding the spatial exclusion effect, which is one of the main points of the effect of the present invention, the spatial spread of the polymer residue is the most important, and the contribution of the difference in chemical properties derived from the chemical structure is small. That's what it means.

Therefore, the chemical structure of the branched polymer residue R that can be used in the present invention is a necessary condition for ensuring excellent moldability, that is, compatibility with a solvent or various matrix materials, or heat. Although it has plasticity, specifically, aromatic polyether, aromatic polyester, aromatic or semi-aromatic polyamide, aromatic polycarbonate, aromatic polyester resin, aromatic police Aromatic polymers and aliphatic polyethers that contain elements other than carbon, such as sulfide, aromatic polyimide, aromatic polyamide, aromatic polyurethane, aromatic polyurethane, aromatic polyamide, etc. in the polymer main chain. , Aliphatic polyester, aliphatic polyamide, fat Aliphatic polymers whose main chain contains elements other than carbon, such as aliphatic polycarbonates, aliphatic polyester carbonates, aliphatic polyurethanes, aliphatic polyurethane ureas, and aliphatic polyureas, polyethylene, polypropylene, polystyrene, and polymethyl methacrylate , Porimechiruaku Li rate, Porifuweniren, Porifuweniru acetylene, polyunsaturated We vinylene like carbon of - polymer main chain carbon bond has been configured, polysiloxanes, polytitanoxane, poly Jirukonokisan, silica (S i 0 _2), titania ( T i 0 _2), can Jirukonia (Z r 0 ₂₎ polymers such consisting of 4 a or 4 B group element oxygen atoms and carbon except such as is illustrated, among these, a plurality of structures are branched polymer It may be present in residue R. Further, the metal cation complex may be composed of plural kinds of metal cations or plural kinds of ligands.

When the metal cation complex is used in a dispersed state in an aqueous electrolyte solution, such as in the use of a contrast agent as described above, the complex must have water solubility. As used herein, the term "water-soluble" means a property that the complexes dissolve in water without aggregating with each other, or a property that the complexes are dispersed in water without forming a sedimentable aggregated structure. The structure of the branched polymer residue R suitable for imparting such water solubility to the complex is an aliphatic polyether such as polyethylene oxide, an aliphatic polyamide, an aliphatic polyester, an aliphatic polycarbonate, an aliphatic polyester, or the like. Elements other than aliphatic chains and carbon, such as tercarbonate, aliphatic polysulfide, aliphatic polyimide, aliphatic polyamide, aliphatic polyurethane, aliphatic polyurethane urea, and aliphatic polyurea Included in the chain structure. A plurality of these exemplified structures may be contained in one branched polymer residue. As an additional effect of the present invention when the metal cation has the ability to generate fluorescence, when the branched polymer residue R contains an aromatic structure, the structure absorbs light mainly in the ultraviolet or infrared region, and The mechanism that transfers energy to the metal cation can improve the fluorescence intensity. Such an effect is known as an antenna effect (for example, Tanner, SP eta 1; J. Am. Chem. Soc., 96, 706 (1974), Ok amo to, Y. eta 1; Macro mo lecules, vol. 14, p. 17 (1 1981), Sabbatini, N. et al. etal; Coordination Chemistry Rev., Vol. 123, page 201 (1993), etc.), for example, is effective for improving the fluorescence intensity of lanthanide cations. Since the antenna effect is based on the properties of the metal cation complex itself, it is also effective in improving the fluorescence intensity at a low concentration at which concentration quenching does not pose a problem. The preferred structure of the branched polymer residue R from the viewpoint of the antenna effect is a structure having absorption in the ultraviolet to infrared region, for example, an aromatic polyether, an aromatic polyester, an aromatic or semi-aromatic polyamide, or an aromatic polycarbonate. , Aromatic polyester polyester, aromatic polysulfide, aromatic polyimide, aromatic polyamide, aromatic polyurethane, aromatic polyurethane urea, aromatic polyurea, etc. Aromatic polymer, polyphenylene, polyphenylene acetylene, polyphenylene vinylene, etc., composed of one unit of an aromatic ring-containing monomer contained in the chain. And an aromatic conjugated polymer composed of A plurality of these exemplified structures may be contained in one branched polymer residue.

 In addition, when the metal cation complex or the polymer composition containing the metal cation complex is used for near-infrared fluorescence, for example, when used as a material for an optical amplifier, an overtone of a vibration mode derived from a carbon-hydrogen bond is required. May appear in the near-infrared region (for example, around 1.5 m), which is a noise component. In order to avoid such inconveniences, it is preferable to replace all hydrogen atoms bonded to carbon atoms in the structure of the branched polymer residue R with another element, for example, a haeogen or deuterium such as fluorine-chlorine. It may be preferred.

 (Structure of branched polymer residue R)

The branched polymer residue R in the ligand, which is a component of the metal cation complex represented by the general formula (2), needs to have a specific molecular weight distribution. That is, between the number average molecular weight Mn (GPc ₎ and the weight average molecular weight Mw ( _GPC) measured by the _{gel permeation chromatography} ( _{GPC) method} , 300 ≤Mn ( _Gl > _c ) ≤ It is desirable that the two relations of 500 000 and 1.0 ^ Mw (ope, / Mn ( _{G PC} ) ≤ 15 be satisfied at the same time. If the value of Mn (G Pc, is less than 300, If so, the spatial extension of the branched polymer residue R is not sufficient, and the above-described space exclusion effect is reduced. If it exceeds 0, it is considered that such a spatial spread is so large that all of them cannot be located near the metal cations.In either case, cluster formation is likely to occur, which adversely affects the effect of the present invention. There is. Therefore, the value of Mn ( _GPC ) is more preferably not less than 400 and not more than 400, more preferably not less than 450 and not more than 200, most preferably not less than 500. The following is assumed.

On the other hand, if the value of Mw ( _GPC ) / Mn _(GPC ,) exceeds 15, the spatial spread of the branched polymer residue R becomes too large, and as a result, the spatial exclusion effect varies greatly. Therefore, cluster quenching may occur easily, and concentration quenching may occur when the metal cation has fluorescence.Therefore, the smaller the value of Mw, »/ Mn (GPc, From this viewpoint, the most suitable branched polymer structure is a dendrimer, and the dendrimer is as described above. Due to the dendritic branch structure, the value of Mw ( _GPC ) ZMn ( _GPC > can be made extremely small. For example, the Frechet described above or the C 0 n ergent method described in the literature by Kakimoto ( De According to the method of constructing one molecule of the dendrimer from the outer block toward the center), it is possible to set the value to 1.0 in principle, while the DiVergent method (one molecule of the dendrimer from the center) (The method of constructing outwardly), it can usually be about 1 to about 2. Therefore, the value of Mw (ope, / Mn,) is more preferably 1.0 to 1 2 The value is more preferably 1.0 or more and 9 or less, most preferably 1.0 or more and 5 or less.

It is preferable that the ligand has at least one branched polymer residue R having a hyperbranched (Hyperbranch) molecular structure. Here, the hyperbranched molecular structure is a dendritic branched molecular structure, and is, for example, a concept typified by the above-mentioned Hawker, Tomalia, Frechet, or dendrimer described in detail in each document by Kakimoto et al. However, there is no restriction on the molecular weight here. If the hyperbranched molecular structure is more strictly defined, the starting point of branching (that is, the above-mentioned focal point) can be specified, and when the molecular chain is traced from the focal point toward the molecular end, the force of force is determined. The molecular structure has at least one molecular end that passes at least one branch point other than the report point.

The complex-forming functional group ^Xn in the ligand is not a component of the hyperbranched molecular structure between the branched polymer residue R and the focal point atom of the branched polymer having the hyperbranched molecular structure. Are desirably linked via the atoms bonded in series. This is presumably because the branching of the branched polymer becomes denser outward from the metal cation located at the center of the complex in order to exhibit an efficient space exclusion effect. The atoms connected in series here have a straight-chain structure, and there are no restrictions on the constituent elements. It is considered that the spatial or chemical environment near the metal cation can be changed by controlling the number of atoms or the kind of element connected in series. When the number of the atoms bonded in series is 50 or more, the shielding effect of the hyperbranched molecular structure in the ligand may be reduced, which is not preferable. More preferably, the number is 40 or less. It is more preferably at most 30 and most preferably at most 25. When utilizing the fluorescence of the metal cation of the complex, it may be preferable that the number of the atoms connected in series is small from the viewpoint of the efficiency of the antenna effect of the ligand.

 (Degree of branching of branched polymer residue)

 It is desirable that the branched polymer residue R has as high a degree of branching as possible as long as the thermoplasticity of the metal cation complex and the compatibility with the solvent or the matrix material are not impaired. This is because, when considering polymers having the same monomer (repeating unit) structure and the same molecular weight, the larger the number of branch points, the higher the conformation with a high space exclusion effect that hinders the approach of the cations. It is thought that it is easy to take. In other words, as it approaches a linear polymer without branching, it can change from a thread-condensed conformation with high space exclusion effect to a low-conformation conformation with extended polymer chains. As a result, the probability that the cations approach each other increases. From this viewpoint, a preferred branched structure is the above-described hyperbranched molecular structure, and among them, the above-mentioned dendrimer structure is most effective.

Furthermore, when the metal cation complex is used as a contrast agent, the viscosity can be reduced by adopting a dendrimer structure, and the convenience in use is excellent. Can be obtained.

 The means for quantifying the degree of branching of the polymer is as described above.

 (Method for producing metal cation complex)

 The metal cation complex represented by the general formula (2) is a carboxylate derivative derived from a polyaminocarbonic acid having a tertiary amino group and a carboxyl group, which are a complex forming functional group in the metal cation and the ligand. And a coordination bond between the metal cation and the tertiary amino group or the carboxyl group in the ligand. The formation of such an ion bond is possible by the exchange reaction of the ion. More specifically, a strong acid salt of the metal cation (for example, a salt with an anion such as chloride ion, bromide ion, iodide ion, fluoride ion, sulfate ion, nitrate ion, and phosphate ion); A method in which a carboxyl group in a metal is converted to a salt of a strong base (eg, a metal ion such as sodium ion, lithium ion, or lithium ion), formic acid, acetic acid, A method of mixing and heating a lower carboxylic acid salt such as oxalic acid and propionic acid with the ligand in the form of a polycarboxylic acid to remove the lower carboxylic acid generated from the raw material salt can be used. The method is not limited to this, and any method may be used.

 (Contrast agent)

 When the metal cation complex represented by the general formula (2) is used as a contrast agent, the above applies.

 (Polymer composition)

It is also possible to disperse the metal cation complex represented by the general formula (2) in a polymer matrix to obtain a polymer composition. In this case, the concentration of the cation in the polymer composition is not particularly limited for the purpose of optical use as long as the transparency required for the use is maintained. It is preferable that the amount is 0.01 to 10% by weight based on the total amount of the cationic complex. If the cation concentration is less than 0.01% by weight, the effect of the present invention, such as an increase in the refractive index or the ability to generate fluorescence, becomes insufficient. In some cases, the mechanical properties such as the molecular composition become extremely brittle and the decrease in mechanical properties becomes remarkable. Not good. From this viewpoint, the more preferable cation concentration is 0.05 to 7% by weight, more preferably 0.1 to 5% by weight, and most preferably 0.5 to 4% by weight.

 A general feature of the polymer composition in which the metal cation complex is dispersed in a polymer matrix is an extremely good dispersion of the cation which is not found in conventional materials. This is because the space exclusion effect of the metal cation complex is maintained to some extent even in the process of producing such a polymer composition, and specifically, for example, in an image observed by a transmission electron microscope. Exemplified is that the proportion of clusters in contact with the cations is less than 20%, more preferably less than 10%, further preferably less than 7%, and most preferably less than 5%.

 There is no particular limitation on the type of polymer matrix used for the polymer composition containing the metal cation complex. However, for the purpose of optical use, it is desirable that the compatibility with the metal cation complex is good in order to maintain the transparency required for the use. In other words, when the metal cation complex is dispersed, in order to achieve transparency for light in the ultraviolet to infrared region, which is considered to be practically important, a dispersion smaller than the wavelength of such light is achieved. It is necessary. More specifically, for example, in observation with a transmission electron microscope, it is desirable that the size of the aggregate of the cations be 20 Onm or less.

 The aggregate referred to here is a cluster in which metal cations are in direct contact with each other, or a state in which the cations considered to be a group formed by association of the metal cation complex are close to each other at a distance of about several nm or less. is there. From the viewpoint of the transparency of the polymer composition or the reduction of concentration quenching in the process of generating fluorescence, the smaller the aggregate, the more preferable. The aggregate is not formed and each cation is uniformly dispersed in the composition. Needless to say, this state is ideal for the purpose of the present invention.

Suitable polymer matrices depend on the chemical structure of the branched polymeric residues that make up the dispersed metal cation complex, but if they are organic, the compatibility, processability, economics, and the matrix itself Polystyrene, polymethyl methacrylate, aromatic polyesters, aromatic polycarbonates, aromatic polyester carbonates, semi-aromatic polyamides, amorphous polyolefins, Known resin materials such as aliphatic polyethers such as ethylene glycol, aromatic or aliphatic polyurethanes, aromatic or aliphatic polyurethane ureas, aromatic or aliphatic polyureas, and aromatic polyimides are suitably used. The molecular weight distribution and branched structure of such a matrix polymer are not particularly limited as long as excellent moldability is maintained.

 The method for producing the polymer composition of the present invention by mixing the metal cation complex and the polymer matrix is not particularly limited. For example, a method of mixing and then drying the mixture in a solution to obtain a composition, a method of using a device for mixing in a molten state such as a single screw extruder, a twin screw extruder, or a Brabender can be exemplified. Among them, a method of mixing in a solution is effective in reducing the aggregate of the cations. Further, in the polymer composition of the present invention, a plurality of kinds of the cations, a plurality of kinds of metal cation complexes, or a plurality of kinds of polymer matrices can be used.

 The metal cation complex or the polymer composition containing the metal cation complex is used for a wide range of applications in which various functions of the cation are applied. For example, a high-brightness fluorescent coating material with extremely stable storage stability that does not cause problems such as the formation of precipitates in the inorganic phosphor dispersion liquid by preparing a solution utilizing its excellent solvent solubility If this is applied to the outer surface of a molded article of any shape, such as a flat surface, a curved surface, or a pipe, it can be used for various displays such as fluorescent road signs, safety signs, license plates, and safety display seals. Protective parts and protective equipment for ensuring traffic safety, such as boards (paper), helmets, bumpers, rain gear (rain flaps, umbrellas, etc.), lighting equipment such as fluorescent lights, and X-ray intensifying screens etc. The product is advantageously obtained. There is no particular limitation on the type of solvent used for such a coating material, but the use of a low-toxic solvent such as water or alcohol is required from the standpoint of environmental protection, which has been particularly required in recent years. In this case, it is necessary to prepare a metal cation complex containing a ligand having good compatibility with such a solvent.

Further, the metal cation complex of the present invention or the composition thereof may be used as a fluorescent labeling agent for, for example, Fluoromenoassay, a lens utilizing an increase in refractive index, an optical waveguide material having a refractive index change in the thickness direction, or an optical waveguide. Near-infrared fluorescence that is important for communication technology (eg For example, an optical communication member such as an optical amplifier using a lanthanide such as Ρr ^3t Nd ³⁺ Dy ³⁺ , Er ³⁺ having a wavelength of 1.3πι or 1.5 // m), It is very useful to apply it as a laser transmitter. In addition, Ho ^{3 +} Er ^{3 +} Tm ³⁺ etc. are the materials of Ab Comparison Laser, and what is £ 11 ²⁺ゃ 丁 ^) ³⁺ etc.? Pr ³⁺ Sm ^2l Eu ³⁺ etc. are useful elements for optical information recording materials utilizing the hole-burning phenomenon, while P t ²⁺ P t are used for visible light isolators using arad ay rotation. ^A cation having a high atomic number such as ³ Au Au ² Au ³⁺ Pb ² Pb "Bi ³ is useful in terms of increasing the refractive index and radiation absorbing ability. It can be usefully used as an optical member material.

 In practical use of the metal cation complex of the present invention or the polymer composition containing the same, any additive may be used as long as the purpose of the present invention is not significantly impaired, such as an organic phosphorus compound such as trioctyl phosphoxide. It is also possible to use an additive or the like that suppresses a decrease in the fluorescence intensity by coordinating with a cation. Example

 Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples as long as the gist is not exceeded.

 [Measuring equipment and conditions]

 (1) GPC: TSK gel manufactured by Tosoh Corporation (grade for molecular weight of about 10,000 or more: GMH XL, grade for molecular weight of about several hundred to 10,000: G-2000), developing solvent: tetrahydrofuran (THF), measurement temperature : 40 ° C, control: monodisperse polystyrene, detection: refractive index change.

(2) NMR: JEOL Ltd. J NM-EX 270 type ^{FT- NMR (Ή 270 MHz, 13} C 67. 8MH z), solvent: CDC 1 ₃

 (3) FT-IR: Measured by preparing a cast film of a methylene chloride solution of the sample on FTZ IR-8000 type FT-IR, salt or KBr crystal manufactured by JASCO Corporation.

(4) Mass spectrum: KOMP ACT MALD I レ ー ザ type laser manufactured by Shimadzu Corporation —Ionized TOF—MS was used. Cation was detected using 3-indole acrylic acid as the matrix material. The measured values were used without any cation correction or the like. (In principle, MALDI measurement is observed in a form in which alkali metal cations such as Na ⁺ and K + are added to the molecular peaks, so correction is performed by assuming a reasonable cation atomic weight. For example, see Leon, JWeta 1 .; Polym. Bull., 35, 4449 (1995).)

 (5) Proton relaxation measurement: JEOL MU-25 (25 MHz) Example 1: Polybenzylether terdendrimer complex

Hawker, C. J. eta 1; J. Am. Chem. Soc., Vol. 112, pp. 736 (199), the fourth generation Dendritic benzyl bromide (abbreviated in the literature as [G-4] —Br) was synthesized. In contrast, by the action of a large excess of ammonia in as tetrahydrofuran (THF), corresponding Dendoriti Kkubenjiruami Namin having Amino group to the focal Boyne Doo (hereinafter [G- 4] -NH ₂ approximately) was converted to. This is reacted in diethylene (2 anhydride DTP A) tri Ύ Minpen evening Aseti Kkujianhai dry de, two molecules of [G-4] binding -NH ₂ via the ami de bound to DTPA one molecule The obtained compound was obtained (hereinafter abbreviated as DTP A— [G—4]). This gave a signal of aromatic and benzyl positions derived from the dendrimer structure, and a signal of a methylene group derived from the DTPA structure, in the NMR spectrum.

Incidentally, [G- 4] -NH ₂ and DTPA- [G- 4] ₂ of GP results of C measurement and Masusu Bae-vector measurement, and the value of Mw / Mw _(GPC), which is calculated from those in Table 1 Summarized.

 [Synthesis of Lanthanide Complex]

Above DTP A— [G—4] and lanthanide (hereinafter abbreviated as Ln) triacetate anhydride (hereinafter abbreviated as LNA c, commercially available hydrate is heated under nitrogen stream to remove the anhydride. Was mixed at a molar ratio of 1Z1. This is violently stirred in black benzene. The mixture was heated under reflux for 2 hours while stirring, and the generated acetic acid was continuously distilled off. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain a complex (hereinafter, abbreviated as Ln-DTPA- [G-4] _{2 of the} general formula). In order to avoid moisture absorption, silica gel was stored in a desiccator containing a desiccant overnight under a nitrogen atmosphere until it was used for the fluorescence measurement experiment. Thus obtained complexes, FT-ingredients in IR spectrum DTP A- [G- 4] exhibited absorption attributed had disappeared to a carbonyl group of the carboxylic acid was observed at _2, 'H and ¹³ C- Since no signal attributable to the acetyl group was found in the NMR spectrum, and the elemental analysis value was consistent with the calculated value within 1% error, the acetyl group of LNAc in the raw material was completely DTP A — It was concluded that the carboxylic acid in [G-4] ₂ was substituted and converted to the target complex.

L n ^{3 +} of the type used, and ash analysis of the corresponding complex (ash calculated as L n ₂ 0 ₃₎ are summarized in Table 2. As a comparative example, a terbium complex of diethylenetriaminepentaacetic acid (DTPA) (hereinafter abbreviated as Tb-DTPA) was adopted, and the fluorescence intensity in a THF solution was the same as that of Tb-DTPA- [G-4]. When compared by concentration, Tb—DTPA— [G—4] ₂ gave stronger fluorescence intensity. Table 1: Analytical values of synthesized dendrimers

Substance w Mn (GPo w (Gpo / Mn ₍ Mw / w

_{[G-4] - NH 2} 3020 2960 1.02 1.1

DTPA-[G-4] 5620 5300 1.06 1.2

Table 2: Synthesized complexes Ln—DTPA— [G—4] ₂ types and ash analysis Ln ash (% by weight)

 Theoretical value Actual measurement value

 P r 2.33 2.30

 N d 2.38 2.46

 E u 2.48 2.55

 Gd 2.56 2.47

 Tb 2.58 2.59

 Dy 2.63 2.54

 H o 2.66 2.59

 E r 2.69 2.74

 Tm 2.72 2.75

 Yb 2.77 2.71 Example 2: Hydrophilic complex A

 [Synthesis of hydrophilic ligand]

Newcome, GR, eta 1 .; According to the method described in Macromolecules, 24, 1443 (1991), tris (hydroxymethyl) aminoaminomethane and acrylonitrile were used as raw materials. Lis {(2-cyanoethyl) oxymethyl} amino methane (hereinafter abbreviated as TCN) and tris {(2-ethoxycarbonylethyl) oxymethyl} amino methane (hereinafter abbreviated as TEC) were synthesized. The amino group of TEC is protected with a t-butoxycarbonyl group (BOC group) by a conventional method using di-t-butyldicarbonate, and then the corresponding tricarboxylic acid (hereinafter referred to as BOC—) is obtained by hydrolysis of the ester using sodium hydroxide. TC). Further, based on the peptide synthesis reaction using 1-hydroxybenzotriazole and dicyclohexylcarpoimide (DCC) described in Newcome et al., TCN was converted to tetrahydrofuran (THF) for BOC-TC. ), One molecule of BOC-TC and three molecules of TCN are amide-bonded (Hereinafter abbreviated as BOC—TC—TCN ₃ ). BOC-TC- the BOC group TCN _3, amine obtained by removing the Torifuruoro acetate in THF as a catalyst (hereinafter TC- T CN ₃ substantially), diethylenetriaminepentaacetic § Sethi Kkujianhai dry de

Reacted (2 anhydride DTPA), two molecules TC TCN ₃ to obtain a compound attached via amino linkage thereof to DT PA one molecule (hereinafter DTP A- CN ₁₈ substantially). Disperse DTP A-CN, ₈ in a large excess of glycerol, stir at 60 ° C while blowing in dry hydrogen chloride gas, convert nitrile groups to glycerol esters, and neutralize with basic ion exchange resin To remove chloride ion. The ion-exchange resin was removed by filtration, 3 equivalents of sodium hydroxide were added to DTPA, and then glycerol and water were distilled off under reduced pressure to obtain a hydrophilic dendrimer having DTPA trisodium salt at the molecular center. The residue mainly consisting of (NNa—DTP AD) was obtained.

 [Synthesis of gadolinium complex]

The above 3Na_DTPA-D and commercially available gadolinium chloride (ΙΠ) hydrate are heated at 170 ° C for 30 minutes under a nitrogen stream to obtain an equimolar amount of anhydrous salt, and then mixed in water. The mixture was heated under reflux to obtain an aqueous solution containing a trivalent gadolinium cation (Gd ³⁺ ) complex of a hydrophilic dendrimer having DTPA at its molecular center and sodium chloride. This complex can obtain a strong MRI signal intensity and is useful as an MRI contrast agent. Example 3: Hydrophilic complex B

 Synthesis of water-soluble ligands]

 The TEC (2.2 equivalents) obtained in Example 2 was combined with diethylenetriamine pen acetic acid anhydride (DTPA dianhydride, 1.0 equivalent) and N, N-dimethylformamide (DMF). The reaction was carried out in the presence of medium pyridine (4.2 equivalents) to obtain a compound in which two molecules of TEC were bound to one molecule of DTPA via an amide bond (hereinafter abbreviated as DTP A—Et 6). The product is silica gel column chromatography

(Developing solvent: acetone-Z methanol mixed system).

 [Synthesis of gadolinium complex]

To a methanol solution of DTP A—Et 6 (1.0 equivalent), An ethanol solution of potassium hydroxide (KOH: 3.0 equivalents) was added, and the anhydrous salt of gadolinium chloride (ΠΙ) used in Example 2 (1.0 equivalent) was added as an aqueous solution, followed by stirring at room temperature for 1 hour. Concentrated. The residue was dissolved in methylene chloride, filtered, concentrated again, and dried in a vacuum oven at 50 ° C to obtain hydrophilic complex B. Example 4: Hydrophilic complex C

 Synthesis of Homi aqueous ligand]

The TEC (3 equivalents) obtained in Example 2 was mixed with BOC-TC (1 equivalent), and 1- (3-dimethylaminopropyl) -3-ethylcarposimid hydrochloride (3.3 equivalents) And stirred in methylene chloride at room temperature for 12 days. Silica gel column chromatography grayed Rafi was purified (developing solvent hexane / acetone mixed system to n-), compound TEC of 3 molecules BOC one TC of 1 molecule has amino linkage thereof (hereinafter BOC-TC- TE C ₃ substantially) I got BOC-TC- the BOC group TEC _3, amine obtained by removing the Torifuruoro acetic acid in THF as catalyst (hereinafter TC one TEC ₃ substantially, 2.0 eq), diethylenetriaminepentaacetic § Sethi Kkujianhai dry de (DTPA Diacid anhydride, 1.0 equivalent), and heated and stirred at 50-70 ° C for 3 days in the presence of pyridine (4 equivalent) in acetonitrile, followed by silica gel column chromatography (developing solvent: methanol). purification by Z § Se Bokun mixed system), two molecules of TC one TE C ₃ to obtain a compound attached via amino linkage thereof to DTP a one molecule (hereinafter DTP A- E t 18 substantially) .

 [Synthesis of gadolinium complex]

An aqueous solution of sodium hydrogen carbonate (3.0 equivalents) was added to the above aqueous solution of DTP AE t18 (1.0 equivalents), and the anhydrous gadolinium chloride (塩 化) used in Example 2 (1.0 equivalents) was added. ) Was added as an aqueous solution, stirred at room temperature for 45 minutes, and concentrated. The residue was shaken with methylene chloride and water, and the organic phase was separated, dried (using anhydrous sodium sulfate), filtered and concentrated. This was dissolved in a large excess amount of 2-aminoethanol, stirred at 90 ° C for 4 hours under a nitrogen stream, and then concentrated under reduced pressure. The methanol solution of the residue is converted to a strongly acidic ion-exchange resin (Mitsubishi Chemical's Diaion PK 216 L, Was used to remove traces of 2-aminoenol and then filtered and concentrated. From the NMR and IR spectra of the hydrophilic complex C thus obtained, it was found that the end of the ester was converted to an amide of 2-aminoethanol. Example 5: Hydrophilic complex D

 Synthesis of water-soluble ligands]

The TEC (3 equivalents) obtained in Example 2 was mixed with BOC-TC (1 equivalent), and the mixture of 1- (3-dimethylaminopropyl) -13-ethylcarposimid hydrochloride (3.3 equivalents) After stirring for 12 days at room temperature in methylene chloride, the product was washed with water, dried (using anhydrous sodium sulfate), filtered, and then concentrated to obtain a product from which water-soluble by-products had been removed. NMR confirmed that the product thus obtained was a mixture of one molecule of BOC-TC and two or three molecules of TEC bonded to the amide (the product having this hyperbranched structure was hereinafter referred to as HB P—short for NHBOC). HBP-NHBOC has a ratio of weight average molecular weight Mw ( _GPC) and number average molecular weight Mn ( _GPC > ₎ obtained by _GPC measurement, where Mw ( _GPC) / Mn (G Pc, is approximately 2. dendrimers not one but have a hyperbranched岐分Ko structure was confirmed. in THF Torifuruoro acetic acid BOC group HB P- NHBoc were removed as a catalyst (a product, hereinafter HBP- NH ₂ approximately). HBP- an amino group of NH ₂ was determined by titration, (2 anhydride DTP a) the amino group 2.0 and for the equivalent 0 equivalents of diethylene tri amine Npentaseti Kkujianhai dry de mixed, Asetonitoriru in pyridine (4 equivalents), continue heating and stirring at 50 to 70 ° C for 3 days, purify by silica gel gel ram chromatography (developing solvent: methanol-Zaceton mixed system), and obtain two molecules of HBP- A compound in which NH ₂ was bound to DTPA via an amide bond was obtained ( DTPA—HBP ₂ ).

 [Synthesis of gadolinium complex]

The carboxyl group content of the above DTP A—HB P ₂ was determined by titration, and an aqueous solution of sodium hydrogen carbonate (3.0 equivalents) was added to 1.0 equivalent of the DTP A ring, which was used in Example 2 here. An anhydrous salt of gadolinium chloride (ΠΙ) (1.0 equivalent) Then, the same operation as that of obtaining the hydrophilic complex C of Example 4 was performed to further apply 2-aminoethanol. From the NMR and IR spectrum of the hydrophilic complex D thus obtained, it was found that the end of the ethyl ester was converted to an amide of 2-aminoethanol. With respect to the aqueous solutions of the hydrophilic complexes of Examples 3, 4, and 5, the longitudinal relaxation (R 1) and the transverse relaxation (R 2) of the proton at 37 ° C. were measured, respectively, and are summarized in Table 3. As a control, magnepist (a gadolinium (1) complex of DTP A, manufactured by Schirring) was used. Table 3: Proton relaxation R1 and R2 of hydrophilic complex (unit: mM—'sec_ ') Substance R1 R2

 Hydrophilic complex B 6. 1 7.1

 Hydrophilic complex C 9.3 1 0

 Hydrophilic complex D 8.9.9.4

 Magnepist 3.9 3.6 Example 6: Acute toxicity test

 The compound prepared in Example 4 was administered to an SD rat (male, 5-week-old body weight: 130 to 140 g, Nippon Chars River Co., Ltd.) at 500 mg / kg (10 m1 Zkg physiological saline). Saline solution) using a 2.5 ml syringe via the tail vein. The general condition was observed for 8 days immediately after the administration, and changes in body weight were measured. The animals were then dissected to observe the changes due to drug administration.

 No deaths were observed due to administration of this compound, and there were no changes in general symptoms and body weight throughout the observation period. No abnormalities were observed in the post-dissection examination. Example II: Contrast effect by the compound of Example 4

Under urethane anesthesia, an SD rat (male, 5-week-old body weight 130-140 g, A silicone tube was force-neutralized into the trachea of Mr. Charlriver and connected to the human respiratory tract. Immediately, the respirator was activated to maintain respiration, and spontaneous respiration was stopped by injecting approximately 0.1 ml 1 Zkg of Myoblock injection (Organon Sankyo) intraperitoneally. Next, force neutrination for administration of the compound was performed on the right lower leg vein, and a surface coil for proton was applied to the upper abdomen of the rat to fix the liver and kidney parts, and fixed. The MR images were measured using a GE 2-tesla horizontal bore (10 cm) system. The measurement was performed by injecting 100 mg of this compound in a saline solution at a rate of 0.4 ml (0.1 mm o 1 / kg) from a force-nucleation tube, and performing gradient echo method (T1 emphasis). Using TE = 8 ms, TR = 80 ms, FOV 50 x 50 mm, slice thickness 2 mm, Flip angle 90 °, under forced breath hold with the ventilator stopped for 30 seconds, The number of integrations was two.

 As a result, a good contrast effect was observed on the liver and kidney images. A good histological image including the running of blood vessels was obtained in the liver immediately after the administration, and a histological image that could identify the internal structure of the kidney that was difficult in the non-administered rat, indicating a high contrast effect. Also, a high contrast effect was observed in the bladder 30 minutes after administration, suggesting that urine excretion was rapid. Industrial applicability

(1) The contrast agent of the present invention comprising a metal cation and a ligand having a hyperbranched molecular structure disperses the metal element extremely stably at the molecular level in the bloodstream, and thus has excellent safety. is there. In addition, since the rotational motility of the complex is extremely suppressed, the complex has a large rotational correlation ( _R ), and is a contrast agent suitable particularly for MRI technology, and its industrial utility value is extremely large. hole.

 Further, the contrast agent comprising a ligand having a hyperbranched molecular structure of the present invention is very excellent in convenience at the time of use due to its low viscosity property.

(2) The metal cation complex according to the present invention comprises a metal cation and a complex forming functional group. It is composed of a certain tertiary amino group and a branched polymer having a polyaminocarboxylate anion having a carboxyl group by electrostatic interaction or coordination bond. Excellent solvent applicability, thermoformability, light weight, toughness against bending displacement, adhesion to a wide variety of substrates, etc. This is a metal cation-containing material that also has In addition, since it is possible to contain an element having a high atomic number in a wide concentration range, it is useful as an optical material having a controlled refractive index used in lenses, optical waveguides, etc., and utilizes the X-ray absorption ability of the element. It is also useful as an X-ray contrast agent, and since it is an ionic compound, a polymer composition or coating agent using the same also has an electromagnetic wave shielding ability and an antistatic ability.

 (3) If a metal element having a fluorescent property is selected, a material having a high fluorescent property with suppressed concentration quenching can be obtained. As a high-brightness fluorescent coating material with excellent storage stability that can be used for molded products such as fluorescent lamps, road signs, and safety signs, or as a fluoroelastomer (f1 uor 0 imm unoassay) It is a material that can be used for a wide range of fluorescent applications, such as fluorescent labeling agents used in applications such as optical amplifiers, optical communication members such as optical amplifiers, and laser transmitters.

 (4) Further, when the cation has paramagnetism, it is also useful as a contrast agent used for imaging (MRI) utilizing a nuclear magnetic resonance (NMR) phenomenon.

Claims

The scope of the claims

I. A complex consisting of a metal cation and a ligand having a hyperbranched molecular structure, wherein the complex-forming functional group in the ligand is located between the focal point atom of the hyperbranched molecular structure and the hyperbranched molecular structure. A contrast agent comprising, as an essential component, a complex that is bonded through 0 or more and 50 or less atoms connected in series, which is not a component of the above.

 2. The contrast agent according to claim 1, wherein the ligand is water-soluble.

3. The contrast agent according to claim 1, wherein the ligand has an active hydrogen atom-containing functional group or a polyalkylene oxide group at a terminal of the hyperbranched molecular structure.

4. The ligand according to any one of claims 1 to 3, wherein the ligand has a hydroxyl group or a polyalkylene oxide group having a repeating unit of 4 or less carbon atoms at the terminal of the hyperbranched molecular structure. Contrast agent.

 5. The method according to any one of claims 1 to 4, wherein the ligand contains an element arbitrarily selected from the group consisting of oxygen, nitrogen, sulfur, and phosphorus in the hyperbranched molecular structure. The contrast agent described.

 6. The hyperbranched molecular structure according to any one of claims 1 to 5, wherein the ligand contains a structure arbitrarily selected from the group consisting of ether, ester, amide, and tertiary amine in the hyperbranched molecular structure. The contrast agent according to Item.

 7. The contrast agent according to any one of claims 1 to 6, wherein the ligand has a porphyrin ring.

 8. The contrast agent according to any one of claims 1 to 7, wherein the hyperbranched molecular structure has a molecular weight of at least 300 and no more than 500,000.

 9. The contrast agent according to claim 8, wherein the hyperbranched molecular structure has a dendrimer structure.

 10. The imaging method according to any one of claims 1 to 9, wherein two or more focal point atoms of the hyperbranched molecular structure are contained on average for one metal cation. Agent.

II. The metal cation is a cation of an element belonging to the sixth period of the periodic table. Item 10. The contrast agent according to any one of Items 1 to 10.

 12. The contrast agent according to any one of claims 1 to 10, wherein the metal cation is a trivalent cation.

 1 3. The contrast agent according to claim 11, wherein the metal cation is a cation of gold or platinum.

 1 4. The metal cation belongs to any of groups 3A, 4A, 5A, 6A, 7A, 8, 8, 1B, and 2B in the periodic table The contrast agent according to any one of claims 1 to 10, which is a cation of a transition metal and has paramagnetism.

 15. The contrast agent according to claim 14, wherein the metal cation is a cation of one of manganese, iron, and a lanthanide element.

 16. The contrast agent according to claim 15, wherein the metal cation is a trivalent gadolinium cation.

 1 7. The contrast agent according to any one of claims 1 to 16, wherein the complex is represented by the general formula (1).

M ^{n +} (RA) π ... (1)

(In the above formula, ^{Mn +} represents an n-valent metal cation, RA— represents a monovalent acid anion, n is an integer of 1 to 4, R represents a hyperbranched molecular structure, and Complex formation Represents a carboquinate group or a sulfonate group which is a functional group.)

 1 8. The contrast agent according to any one of claims 1 to 16, wherein the complex is a metal cation complex represented by the following general formula (2).

M ^{n +} (X ^n- ) — R _m … (2)

(In the above formula, M ^{n +} represents an n-valent metal cation, (X ⁿ —) — R _m represents a ligand, and X ⁿ represents a complex tertiary amino group and a carboxyl group. Represents an n-valent carboxylate anion of a polyaminocarboxylic acid having a group, R _m represents an independently branched polymer residue which may be different from each other and binds to X ⁿ —, and n represents 1 to 4 M represents an integer of 1 to 6. The branched polymer residue R is a number-average molecular weight measured by gel permeation chromatography (GPC). Between Mn (G pc,) and the weight average molecular weight, Mw ( _GPC) , 300 0 ≤ Mn ( _GPC ) ≤ 500 000 and 1.0 ≤ Mw, G Pc, / Mn, ≤ 15 Satisfies two relationships at the same time.)

19. The contrast agent according to claim 18, wherein at least one of the branched polymer residues R in the ligand (X ⁿ —) —R _{m has} a hyperbranched molecular structure.

20. At least one of the branched polymer residues R in the ligand (X ⁿ —) -R _m has the true weight average molecular weight Mw and gel permeation measured by the mass spectral method or the light scattering method. 10. The contrast agent according to claim 19, wherein a relationship of Mw / Mw, GPc,> 1 is satisfied between the weight average molecular weight Mw measured by a shion chromatography (GPC) method.

21. Ligand (X ⁿ —) — The contrast agent according to claim 19 or 20, wherein at least one of the branched polymer residues R in R _m is a dendrimer.

2 2. ligands (X ⁿ _) - at least one of the branched polymer residues R in R _m, the first 8 wherein the claims made by the aromatic ring-containing monomer unit to the second item 1 The contrast agent according to any one of the first to third aspects.

 2 3. A complex consisting of a metal cation and a ligand having a hyperbranched molecular structure, and a complex-forming functional group in the ligand is located between the focal-point atom of the hyperbranched molecular structure and a hyperbranched molecule. A pharmaceutical composition for in-vivo diagnosis, comprising a complex which is not a component of the structure and is bonded via 0 to 50 series-bonded atoms, and a pharmaceutically acceptable carrier.

 2 4. A metal cation complex represented by the general formula (2) according to claim 18.

 25. The metal cation complex according to claim 18 is dispersed in a polymer matrix, and the metal cation concentration is from 0.01 to 10% by weight. Polymer composition.

 2 6. A molded article having the metal cation complex according to claim 18 on an outer surface.

2 7. An outer surface made of the polymer composition described in claim 25 27. The molded article according to Item 26.

 28. A coating material characterized by containing the metal cation complex according to claim 18.