JP3404787B2 - Novel diethylenetriaminepentaacetic acid derivative, complex compound of the derivative with a metal atom, and diagnostic agent containing the complex compound - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel diethylenetriaminepentaacetic acid (hereinafter referred to as DTPA) derivative, a complex compound of the derivative and a metal atom, and a diagnostic agent containing the complex compound. More specifically, the present invention relates to a novel DTPA derivative capable of forming a complex with a metal atom, a complex compound comprising the derivative and the metal atom, which is useful for medical diagnosis, and a diagnostic agent containing the complex compound.

[0002]

2. Description of the Related Art At present, an image diagnostic method for diagnosing a lesion by drawing information on a lesion as an image is an indispensable examination for clinical diagnosis. In particular, X-ray CT is one of the diagnostic imaging methods that have been widely used in the past, but in the last decade or so, new outstanding features such as magnetic resonance imaging (hereinafter referred to as MRI) have emerged. Image diagnostic techniques have been developed, and these new techniques have greatly contributed to the development of the image diagnostic field.

Unlike conventional X-ray CT, such MRI is characterized in that it does not require radiation and thus does not have a problem of being exposed to radiation, that it can visualize an arbitrary cross section, and that it does not interfere with bones. This is a technology that has rapidly advanced and spread since it was introduced into the medical field in recent years. MRI images differences in nuclear magnetic resonance phenomena of substances in the body [usually relaxation times (T ₁ , T ₂ ) of hydrogen nuclei] as differences in signal intensity. At this time, paramagnetic substances are protons. It serves as a contrast agent that has a relaxation effect of promoting the relaxation phenomenon of (water protons) and enhances the contrast of images. Among them, gadolinium (trivalent) (hereinafter referred to as Gd), which is a rare earth metal, has a strong relaxation effect because it has 7 unpaired electrons in the 4f orbital and has a large number of coordination sites (9 or 10). Becomes a powerful contrast material [RB Lauffer,
Chem, Rev., 87, 901 (1987)]. However, Gd (3
Value) is not excreted outside the body, so its toxicity is a problem.

Therefore, DTPA (diethylenetriamine-pentaacetic acid), which is a known chelating agent, is actually used.
It is administered as a complex compound with (Gd-DTPA).

[0005]

Gd-DTPA has been confirmed to be useful in clinical diagnosis. However, this drug has problems such as a short half-life in blood, poor tissue selectivity, and high osmotic pressure because it exists as a divalent anion complex under physiological conditions. It contains a lot of power points.

Various approaches have been taken for chelating agents in order to solve these problems (Japanese Patent Laid-Open No. SHO 6-61138).
No. 3-93758, Japanese Patent Laid-Open No. 1-1395, etc.) have not yet obtained sufficient results. Therefore, the development of new complex compounds, especially the development of chelating agents is of great significance.

The object of the present invention is to provide a novel compound capable of forming a complex compound having excellent contrast enhancing ability, tissue selective ability, stability, sustainability in blood, and not exhibiting high osmotic pressure. It is intended to provide a DTPA derivative, a complex compound comprising the derivative and a metal atom, which is useful for medical diagnosis, and a diagnostic agent containing the complex compound.

[0008]

Means for Solving the Problems To solve the above problems, the present inventor has made various studies on chelating agents and the like. As a result, the compound represented by the following general formula (I) and a metal atom are used. It has been found that the complex compound is excellent in contrast enhancing ability, tissue selection performance, stability, sustainability in blood, and does not exhibit high osmotic pressure, and has completed the present invention.

That is, the present invention has the general formula (I):

[0010]

[Chemical 2]

(Wherein A represents alkylene, B represents an aliphatic hydrocarbon group or phenyl having at least an aliphatic hydrocarbon group as a substituent), a DTPA derivative or a salt thereof, the derivative and a metal. The present invention relates to a complex compound containing an atom or a salt thereof, and a diagnostic agent containing the complex compound or a salt thereof.

The symbols used in the general formula (I) will be described below. The alkylene in A preferably has 2 to 5 carbon atoms and may be linear or branched, and examples thereof include ethylene, trimethylene, tetramethylene and pentamethylene.

Examples of the aliphatic hydrocarbon group for B or the aliphatic hydrocarbon group which is a substituent of phenyl include an alkyl group and an alkenyl group.

The alkyl group has 4 to 14 carbon atoms, preferably 6 to 10 carbon atoms, more preferably about 8 carbon atoms, and may be linear or branched. Specific examples include butyl, hexyl, octyl, decyl, dodecyl, tetradecyl and the like.

The alkenyl group has 4 to 14 carbon atoms,
It preferably has 6 to 10 carbon atoms, and more preferably has about 8 carbon atoms, and may be linear or branched, and is not limited to the position and number of double bonds. In particular,
Examples thereof include butenyl, hexynyl, octenyl, decenyl, dodecenyl, tetradecenyl and the like.

The benzene ring represented by B may be substituted with a lower alkyl group, a lower alkoxy group, a halogen atom or a trifluoromethyl group in addition to the above aliphatic hydrocarbon group.

The lower alkyl group preferably has 1 to 4 carbon atoms and may be linear or branched, and specific examples thereof include methyl, ethyl, propyl, butyl and isobutyl. It

The lower alkoxy group preferably has 1 to 4 carbon atoms, and specific examples thereof include methoxy, ethoxy, propoxy, butoxy and the like.

Examples of the halogen atom include chlorine atom and bromine atom.

As the salt of the compound (I) of the present invention, a medically acceptable salt is preferably used. Examples of the salt include salts with metals (sodium, potassium, etc.), organic bases [ethanolamine, morpholine, etc.]. , Meglumine (N-methylglucamine) and the like], and salts with amino acids (arginine, ornithine and the like) and the like.

The compound (I) of the present invention can be produced by various methods. Specifically, for example, it can be prepared by the following method. First, formula (II):

[0022]

[Chemical 3]

And a compound of the general formula (III):

[0024]

[Chemical 4]

(In the formula, X represents a protecting group for an amino group such as a benzyloxycarbonyl group, a t-butoxycarbonyl group and a fluorenylmethyloxycarbonyl group. A and B
Is the same as above. ) Is reacted with a compound represented by

The reaction of the compound (II) with the compound (III) can be carried out according to a conventional method of reacting an acid anhydride with an amino compound. The compound (III) may be used in the form of a salt. For example, a solution of the compound (II) in an organic solvent such as N, N-dimethylformamide may be added to
If necessary, dissolve (III) in an organic solvent such as methylene chloride or chloroform, and add at room temperature to about 90 ° C for 30 minutes to 5 minutes.
It can be carried out by reacting for about a day. In this reaction, a basic compound such as pyridine, triethylamine, N, N-dimethylaniline or the like may be added.

In this reaction, the compound (III) is the compound (I
It is preferable to use 0.8 to 1.2 equivalents to I). In order to obtain the target compound in good yield, the compound (II
It is preferred to add about 1 equivalent of water before adding I).

After completion of the above reaction, the elimination reaction of X, which is an amino group-protecting group, is carried out. Such reaction can also be carried out by a known method. Specifically, when X is a benzyloxycarbonyl group, a catalyst such as palladium / carbon is added to a solution prepared by dissolving the reaction product of the compound (II) and the compound (III) in methanol or the like, and the reaction is performed under a hydrogen atmosphere. 3 at room temperature to 60 ℃
X can be desorbed by stirring for about time to 5 days.

The compound (I) of the present invention can be prepared by the above reaction.

The starting material in the above reaction step, namely D
Compound (II), which is an acid anhydride of TPA, includes DTPA such as acetic anhydride, dicyclohexylcarbodiimide, 1,
It can be obtained by subjecting it to a known dehydration reaction using 1′-carbonyldiimidazole or the like. This reaction is carried out at 50 to 100 ° C. in a solvent that does not adversely affect the reaction.
The reaction can be carried out for about 3 hours to 3 days.

The compound (III) can be prepared, for example, by the following method. First, general formula (IV):

[0032]

[Chemical 5]

(Wherein Y represents an amino-protecting group to the same extent as X. A and X have the same meanings as defined above), and a compound of the general formula (V):

[0034]

[Chemical 6]

(Wherein B is as defined above) is reacted.

In the reaction of the compound (IV) with the compound (V), both compounds are dissolved in an organic solvent such as methylene chloride or chloroform, and a condensing agent such as dicyclohexylcarbodiimide or water-soluble carbodiimide is added to the reaction mixture at room temperature to 6 ° C.
It can be carried out by reacting at about 0 ° C. for about 5 minutes to 1 day.

Then, the elimination reaction of Y which is an amino-protecting group is carried out. This step can also be performed by a known method.
Specifically, when Y is a t-butoxycarbonyl group, an excess amount (10 to 30 equivalents) of trifluoroacetic acid is added to the reaction product of compound (IV) and compound (V) under ice cooling, ℃
After reacting for about 1 to 5 hours, the excess trifluoroacetic acid is distilled off, and the compound of interest (II) is extracted by extracting with an organic solvent such as chloroform or ethyl acetate under alkaline conditions.
I) get

The compound (IV) used here is a method in which two amino groups of diaminomonocarboxylic acid (basic amino acid) are protected by a known method such as a known protecting group (benzyloxycarbonyl group, t-butoxycarbonyl group, fluorine-containing group). It is obtained by protection with an olenylmethyloxycarbonyl group).
Suitable compounds include compounds in which X is a benzyloxycarbonyl group and Y is a t-butoxycarbonyl group. The preparation method itself is, for example, Chemical Abstrac
ts 61 (4) p8405.

The salt of compound (I) can also be prepared by a known method.

The compound (I) thus obtained and its salt can be isolated and purified by a conventional method such as recrystallization, reprecipitation, column chromatography and the like. In addition, when the compound (I) of the present invention has an asymmetric carbon in the molecule, all the optical isomers based on the asymmetric carbon and mixtures thereof are included in the present invention.

The complex compound of the present invention is formed from the above compound (I) and a metal atom. Metal atoms are MRI images,
Those suitable for X-ray images, radionuclide images, etc. are appropriately selected and used according to the type of diagnostic agent and diagnostic method, as described later.

The complex compound can be prepared by a method known in the art. For example, a metal oxide or halide compound may be added to water and treated with an equimolar amount of compound (I) or a salt thereof. The compound (I) and its salt can be added as an aqueous solution, but if solubility in water is concerned, an organic solvent such as methanol, ethanol, acetone, dimethyl sulfoxide or the like may be added. Further, the pH can be controlled by adding a dilute acid or a dilute base as needed. Heating and cooling during the preparation of the complex compound can be appropriately performed.

As the salt of the complex compound of the present invention, a pharmaceutically acceptable salt is preferably used, like the salt of the compound (I). This is because, in the above-mentioned preparation method, while the complex compound is still in a dissolved state, an acid (eg organic acid, inorganic acid etc.) or base (eg alkali metal hydroxide,
It can be produced by neutralizing the complex compound with a basic amino acid).

The diagnostic agent of the present invention comprises the above complex compound or a salt thereof, and by appropriately selecting the metal atom of the complex compound, an MRI diagnostic agent, an X-ray diagnostic agent, a nuclear medicine diagnostic agent, an ultrasonic diagnostic agent, etc. Can be used as Among them, the diagnostic agent of the present invention can be preferably used as an MRI diagnostic agent.

When the diagnostic agent of the present invention is used as an MRI diagnostic agent, the metal atom forming the complex compound is preferably an element having an atomic number of 21 to 29, 42, 44, 57 to 70. The central metal ion of the complex compound needs to be paramagnetic, and divalent and trivalent ions of the metal atom are suitable. Suitable ions include, for example, chromium (I
II), manganese (II), iron (III), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III)
, Samarium (III), terbium (III), dysprosium (III), holmium (III), erbium (III) and ytterbium (III) ions. Especially gadolinium (III), terbium (III), dysprosium (II
I), holmium (III), erbium (III) and iron (III)
Ions are preferred.

When used as a diagnostic agent for nuclear medicine, the metal atom of the complex compound needs to be radioactive, and for example, radioactive isotopes of elements such as gallium, technesium, indium and yttrium are used.

When used as an X-ray diagnostic agent, the metal atom of the complex compound needs to absorb X-rays, and for example, a lanthanide series metal, tantalum or the like is used. Further, these complex compounds can also be used as an ultrasonic diagnostic agent.

The diagnostic agent of the present invention is provided in the form of an aqueous solution, an emulsion, a liposome preparation, a freeze-dried preparation of these. Aqueous solutions and liposome preparations are preferred.
These preparations can be prepared by the conventional means for preparation using the above-mentioned complex compound aqueous solution. The lyophilized preparation is used by dissolving / dispersing it in an appropriate diluent at the time of use.
The diagnostic agent of the present invention contains a physiologically acceptable buffer solution (eg, tris (hydroxymethyl) aminomethane, etc.) and other physiologically acceptable additives (eg, stabilizers such as parabens), etc. You may have.

The complex compound of the present invention and the diagnostic agent containing the complex compound have high lipid affinity and excellent tissue selectivity.
Has concentration. In particular, it has a good balance of accumulation and excretion in the liver, and is useful for diagnosis of liver tumors and the like.

The diagnostic agent of the present invention can be used in the same manner as a conventional diagnostic agent, for example, a liquid agent is orally or parenterally administered to mammals including humans. The dose is substantially similar to conventional diagnostic agents, 0.001
~ 5 mmol / kg, preferably 0.005-0.5 mmol
It is about / kg.

[0051]

EXAMPLES The present invention will now be described in more detail based on Examples, Reference Examples and Test Examples, but the present invention is not limited thereto.

Reference Example 1 Nα-benzyloxycarbonyl-lysyl 4-octyl
Synthesis of luanilide (Z-Lys-OA) Nα-benzyloxycarbonyl-Nε-t-butoxycarbonyl-lysyl-4-octylanilide [Z-Ly
Synthesis of s (Boc) -OA] Nα-benzyloxycarbonyl-Nε-t-butoxycarbonyl-lysyl [Z-Lys (Boc)] (This is synthesized by a known method. Chemical Abstracts 6
1 (4) p8405 etc.) 20.112 g (52.87 mmol)
And 4-octylaniline 11.079g (53.95m
mol) in 100 ml of dichloromethane, and under ice-cooling 11.153 g (58.15 mm) of water-soluble carbodiimide
was added and the mixture was stirred at room temperature for 2 hours. Purification was carried out by a column chromatogram method (eluent: hexane-ethyl acetate) to obtain white crystals of Z-Lys (Boc) -OA in 2
8.396 g (yield 94.6%) was obtained.

[0053] ^{IR (KBr) 3300,1690,1660cm -1 1 H} -NMR (CDCl 3) 0.88 (3H, t, J
= 6.5 Hz), 1.20-1.40 (10H, m),
1.40-1.65 (6H, m), 1.42 (9H,
s), 1.65-1.85 (1H, m), 1.85-
2.10 (1H, m), 2.56 (2H, t, J = 7.
6 Hz), 3.00-3.25 (2H, m), 4.20
-4.30 (1H, br.q), 4.55-4.70
(1H, br.t), 5.12 (2H, s), 5.45
-5.60 (1H, br.d), 7.11 (2H, d,
J = 8.4 Hz), 7.30-7.40 (5H, m),
7.41 (2H, d, J = 8.3Hz), 8.03-
8.25 (1H, br.s) mp 122-124 ° C

Synthesis of Z-Lys-OA Z-Lys (Boc) -OA 28.396 g (50.
(01 mmol) was added to a flask containing ice-cooled trifluoroacetic acid 90 ml (1.168 mol) under ice-cooling, and under ice-cooling 2
Stir for hours. After distilling off excess trifluoroacetic acid,
23.402 g (yield 100%) of white crystals of Z-Lys-OA by extracting with ethyl acetate under alkaline conditions.
Obtained.

[0055] ^{IR (KBr) 3300,1685,1660cm -1 1 H} -NMR (CDCl 3) 0.88 (3H, t, J =
6.4 Hz), 1.20-1.40 (10H, m),
1.40-1.65 (8H, m), 1.65-1.85
(1H, m), 1.85-2.05 (1H, m), 2.
56 (2H, t, J = 7.5 Hz), 2.65-2.8
0 (2H, m), 4.20-4.40 (1H, br.
q), 5.13 (2H, s), 5.45-5.55 (1
H, br. d), 7.11 (2H, d, J = 8.4H
z), 7.35 (5H, s), 7.40 (2H, d, J
= 8.1 Hz), 8.40-8.50 (1H, br.
s) mp 89-91 ° C

Reference Example 2 Nα-benzyloxycarbonyl-lysyl 4-dodecyl
Synthesis of luanilide (Z-Lys-DoA) Nα-benzyloxycarbonyl-Nε-t-butoxycarbonyl-lysyl-4-dodecylanilide [Z-L
Synthesis of ys (Boc) -DoA] Z-Lys (Boc) 27.835 g (73.17 mm)
ol) and 4-dodecylaniline 19.129 g (73.
17 mmol) in 150 ml of dichloromethane,
Water-soluble carbodiimide 15.433 g (80.5
1 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Purification was performed by a column chromatogram method (eluent: hexane-ethyl acetate), and white crystals of Z-Lys (Boc) -Do were obtained.
38.996 g (yield 85.4%) of A was obtained.

[0057] ^{IR (KBr) 3350,1690,1660cm -1 1 H} -NMR (CDCl 3) 0.88 (3H, t, J =
6.5 Hz), 1.20-1.40 (18H, m),
1.40-1.65 (6H, m), 1.42 (9H,
s), 1.65-1.85 (1H, m), 1.85-
2.10 (1H, m), 2.55 (2H, t, J = 7.
6 Hz), 3.00-3.25 (2H, m), 4.20
-4.30 (1H, br.q), 4.55-4.70
(1H, br.t), 5.10 (2H, s), 5.45
-5.60 (1H, br.d), 7.08 (2H, d,
J = 8.4 Hz), 7.32 (5H, br.s), 7.
40 (2H, d, J = 8.3Hz), 8.20-8.5
0 (1H, br.s) mp 117-118.5 ° C

Synthesis of Z-Lys-DoA Z-Lys (Boc) -DoA 40.793 g (6
To the flask containing 5.39 mmol), 100 ml (1.298 mol) of trifluoroacetic acid was added under ice cooling, and the mixture was stirred under ice cooling for 1 hour. After distilling off excess trifluoroacetic acid, the mixture was extracted with ethyl acetate under alkaline conditions to obtain 33.818 g of white crystals of Z-Lys-DoA (yield 9
8.7%).

[0059] ^{IR (KBr) 3300,1690,1660cm -1 1 H} -NMR (CDCl 3) 0.88 (3H, t, J =
6.4 Hz), 1.20-1.40 (18H, m),
1.40-1.60 (6H, m), 1.60-1.80
(1H, m), 1.80-2.00 (1H, m), 2.
53 (2H, t, J = 7.6Hz), 2.60-2.7
5 (2H, br.t), 4.25-4.45 (1H, b
r. q), 5.04 (1H, d, J = 12.3Hz),
5.12 (1H, d, J = 12.2Hz), 5.98
(1H, br.d), 7.06 (2H, d, J = 8.4
Hz), 7.30 (5H, br.s), 7.38 (2
H, d, J = 8.3 Hz), 8.93 (1H, br.
s) mp 91-93 ° C

Reference Example 3 N- [5-carboxy-5- (4-octylbenzoyl)
Amino) -pentylcarbamoylmethyl] diethyleneto
Liamine-N, N ', N ", N" -tetraacetic acid (DTPA-
Synthesis of Lys-OB) Commercially available N [epsilon] -t-butoxycarbonyl lysine [Lys
(Boc)] and 4-octylbenzoyl chloride
-4-Octylbenzoyl-N [epsilon] -t-butoxycarbonyl lysine [OB-Lys (Boc)] is prepared, and then trifluoroacetic acid is used to obtain N [alpha] -4-octylbenzoyl lysine trifluoroacetic acid salt. This is DTP
DTPA-Lys-OB was obtained by reacting with DTPA monohydrogen prepared from A dianhydride and water and purifying by a column chromatogram method.

Example 1 N- [5-amino-5- (4-octylphenylcarba
Moyl) -pentylcarbamoylmethyl] diethyleneto
Liamine N, N ', N ", N" -tetraacetic acid (DTPA-
Synthesis of Lys-OA) Diethylenetriamine pentaacetic acid dianhydride 1 at 80 ° C.
7.866 g (50.00 mmol) of anhydrous DMF25
Dissolve in 0 ml and water 0.901 ml (50.00 mmo
l) was added dropwise, and the mixture was stirred at the above temperature for 1 hour to generate diethylenetriaminepentaacetic acid monoanhydride. 23.402 g (50.04 g of Z-Lys-OA was added to this solution.
(60 mmol) in a dry chloroform solution, and the mixture is stirred for another 2 hours at the above temperature. Purification was performed by a column chromatogram method (eluent: methanol-water) to obtain 17.160 g (yield 40.7%) of monoamide DTPA-Z-Lys-OA (white amorphous).
Obtained. Dissolve this in 800 ml of methanol and add 10% P
3.40 g of d-carbon was added, and the mixture was stirred under a hydrogen stream at 45 ° C for 6 hours. By filtering off Pd carbon and concentrating the filtrate, 13.742 g (yield 95.7%) of white amorphous was obtained.

IR (KBr) 3500-3000,1
^{680,1640,1620cm -1 1 H-NMR (CD} 3 OD) 0.89 (3H, t, J =
6.4 Hz), 1.15 to 1.45 (10 H, m),
1.45-1.75 (6H, m), 1.80-2.10
(2H, m), 2.57 (2H, t, J = 7.5H
z), 3.05-3.20 (2H, m), 3.20-
3.45 (8H, m), 3.39 (2H, s), 3.5
2 (2H, s), 3.70 (6H, s), 4.19 (1
H, t, J = 6.2 Hz), 7.13 (2H, d, J =
8.4 Hz), 7.51 (2H, d, J = 8.4 Hz) mp 180 to 183 ° C

Example 2 N- [5-amino-5- (4-dodecylphenylcarba
Moyl) -pentylcarbamoylmethyl] diethyleneto
Liamine N, N ', N ", N" -tetraacetic acid (DTPA-
Synthesis of Lys-DoA) Diethylenetriamine pentaacetic acid dianhydride 2 at 80 ° C
3.398 g (65.48 mmol) of anhydrous DMF35
Dissolve in 0 ml and water 1.180 ml (65.48 mmo
l) was added dropwise, and the mixture was stirred at the above temperature for 1.5 hours to generate diethylenetriaminepentaacetic acid monoanhydride. To this solution, 34.297 g of Z-Lys-DoA (6
A solution prepared by dissolving 5.48 mmol) in 70 ml of a dry chloroform solution is added, and the mixture is further stirred for 2 hours at the above temperature. Column chromatogram method (eluent: methanol-
Water) to purify the monoamide DTPA-Z-Ly
23.756 g (yield 40.4%) of s-DoA (white amorphous) was obtained. This was dissolved in 800 ml of methanol, 4.798 g of 10% Pd carbon was added, and the mixture was placed in a hydrogen stream 4
The mixture was stirred at 5 ° C for 6 hours. By filtering off Pd carbon and concentrating the filtrate, 19.075 g (yield 93.8%) of white amorphous was obtained.

IR (KBr) 3500-3000,1
^{680,1640,1620cm -1 1 H-NMR (CD} 3 OD) 0.89 (3H, t, J =
6.4 Hz), 1.15 to 1.40 (18 H, m),
1.40-1.70 (6H, m), 1.80-2.10
(2H, m), 2.57 (2H, t, J = 7.3H
z), 3.05-3.25 (2H, m), 3.25-
3.40 (8H, m), 3.49 (2H, s), 3.5
6 (2H, s), 3.70 (4H, s), 3.76 (2
H, s), 4.05-4.30 (1H, m), 7.13.
(2H, d, J = 7.8 Hz), 7.51 (2H, d,
J = 7.6 Hz) mp 192-206 ° C.

Example 3: Preparation of Gd · Compound (I) Complex Compound To an aqueous solution of 1,8.4 g of compound (I) dissolved in 800 ml of distilled water, 200 ml of 0.05 M GdCl ₃ solution was gradually added, and The mixture was stirred while maintaining the pH at around 7.0 by adding a 1N NaOH aqueous solution, and then stirred at room temperature to about 1
Reacted for hours. After the reaction, the reaction solution is freeze-dried and
1.2 g of Gd-compound (I) complex compound was obtained.

Example 4: Preparation of Gd · Compound (I) Fat Emulsion To 10 g of purified soybean oil, 6 g of purified egg yolk phospholipid and 4 g of Gd · Compound (I) complex compound were added and mixed with 17 g.
5 ml of distilled water and 2.0 g of glycerin were added and homogenized with a homomixer. Next, high-pressure emulsification was carried out using a Manton-Gaulin type high-pressure homogenizer to obtain a homogenized extremely fine Gd.
A compound (I) fat emulsion was obtained. Obtained Gd / Compound (I)
The osmotic pressure ratio of the fat emulsion to physiological saline was about 1.0.

Example 5 Preparation of Gd · Compound (I) Liposome 6 g of purified egg yolk phospholipid and Gd · Compound (I) complex compound 4
After adding g, they were mixed, to which 175 ml of distilled water and 2.0 g of glycerin were added, and homogenized with a homomixer. Next, high-pressure emulsification was performed using a Manton-Gaulin type high-pressure homogenizer to obtain homogenized extremely fine Gd-compound (I) liposomes having an average particle size of 1 μm or less. The osmotic pressure ratio of the obtained Gd / compound (I) liposome to physiological saline was also about 1.0.

Test Example 1: Distribution in rat liver The Gd · Compound (I) fat emulsion obtained in Test Example 4 was bolus administered from the tail vein (dosage 0.02 mmol / k).
g). 30 minutes, 1, 2, 4, 6 and 24 hours after administration, the animals were sacrificed with CO ₂ gas, then blood was removed, and the livers were taken out. The liver was freeze-dried for 1 day and then pulverized, and 0.2 g of this was added with 3 ml of nitric acid and heated on a hot plate at 180 ° C. After nitric acid (1 ml) was added to this to dissolve the residue, gadolinium was quantified by ICP (inductively coupled plasma) emission spectrometry with 10 ml of water [analyzer: Shimadzu ICPV-1000, measurement wavelength: 34
2.25 nm (Gd)], and the ratio (%) to the dose was determined. As a result, it was revealed that the Gd.compound (I) fat emulsion has excellent properties of accumulating in the liver and disappearing 24 hours after administration (FIG. 1). Further, the aqueous solution obtained in Example 3 and the liposome obtained in Example 5 had the same characteristics.

Comparative Test 1: G prepared as in Example 3
The distribution in the rat liver was examined in the same manner as in Test Example 1 using the d.DTPA complex compound aqueous solution. The results did not accumulate in the liver and were found to be difficult to use as a diagnostic agent (Fig. 2).

Comparative test 2 Formula (VI) obtained in Reference Example 3:

[0071]

[Chemical 7]

N- [5-carboxy-5-
(4-octylbenzoylamino) -pentylcarbamoylmethyl] diethylenetriamine-N, N ′, N ″,
A fat emulsion was prepared using N ″ -tetraacetic acid (DTPA-Lys-OB) in the same manner as in Example 4, and the distribution in the rat liver was examined in the same manner as in Test Example 1. The results were accumulated in the liver. Without it, it was judged that it cannot be used as a diagnostic agent.

[0073]

INDUSTRIAL APPLICABILITY Compound (I) of the present invention forms a complex compound with a metal atom to provide a complex compound extremely useful for medical diagnosis. This complex compound has properties such as excellent contrast enhancing ability, tissue selection performance, stability, sustainability in blood, and no high osmotic pressure. Therefore, it is useful for medical diagnosis, especially for MRI diagnosis. Useful in. A diagnostic agent containing such a complex compound is predominantly used in imaging various organs, tumor parts, blood vessels, etc., and particularly has excellent balance of accumulation and excretion in the liver, diagnosis of liver tumors, and imaging of bile ducts and biliary tracts. Useful for. The tissue selectivity and concentration of the diagnostic agent of the present invention are in the moderate fat solubility possessed by the compound (I) of the present invention, and the complex compound thereof also retains similar properties, and thus it can be formed into a fat emulsion or liposome. It is possible to improve the tissue selectivity / concentration together with the formulation of drug formulations.

[Brief description of drawings]

FIG. 1 is a graph showing the distribution of Gd · compound (I) fat emulsion (20 μmol / kg) obtained in Example 4 in rat liver over time (0 to 24 hours).

FIG. 2 Gd / DTPA complex compound aqueous solution (20 μmol / k
It is a graph which showed distribution of g) in the rat liver over time (0 to 24 hours).

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI G01R 33/28 G01N 24/02 B (72) Inventor Masakazu Shindome 2-25-1 Otani, Otani, Hirakata-shi, Osaka Midori Co., Ltd. In the Cross Central Research Institute (72) Yuichi Mukai Invited 2-25-1 Otani, Hirakata City, Osaka Prefecture Midori Co., Ltd. (72) Inventor Ikuko Miyagi 2-25-1 Otani Invited, Hirakata City, Osaka Company Midori Cross Central Research Institute (72) Inventor Tsuyoshi Imagawa 2-25-1 Otani, Hirakata, Osaka Prefecture Midori Cross Central Research Institute Co., Ltd. (72) Inventor Kin Naomoto 18-1 Kitagaoka, Suita City, Osaka Prefecture 301 (72) Inventor Tarou Marukawa ▼ Hiroji Honcho, Showa-ku, Nagoya, Aichi 3-1, Pier 3C-4 (72) Inventor Kozuka ▲ Takahiro Suma-ku, Kobe, Hyogo Mamorumachi 2-3-15 (56) Reference Patent Sho 63-93758 (JP, A) (58 ) investigated the field (Int.Cl. ^7, DB name) C07C 237/22 CA (STN) REGISTRY (STN )

Claims (4)

(57) [Claims] 1. A compound represented by the general formula (I): (In the formula, A represents alkylene and B represents phenyl having an aliphatic hydrocarbon group or at least an aliphatic hydrocarbon group as a substituent.) A diethylenetriaminepentaacetic acid derivative or a salt thereof. 2. A complex compound of the diethylenetriaminepentaacetic acid derivative according to claim 1 and a metal atom, or a salt thereof. 3. A diagnostic agent containing the complex compound according to claim 2 or a salt thereof. 4. A liver tumor diagnostic agent comprising the complex compound of the diethylenetriaminepentaacetic acid derivative according to claim 1 and a paramagnetic metal or a salt thereof.