JPH03197468A - Bifunctional large cyclic chelate ligand and its preparation - Google Patents

Abstract

NEW MATERIAL:A bifunctional large cyclic chelate ligand of formula I (Z is a functional group capable of combining with a biological substance or a functional group capable of being converted into the functional group; A is 1-10C divalent hydrocarbon; R<1> is 2-9C linear chain or branched chain divalent hydrocarbon group; Y is a group of formula II; R<2> is 2-9C linear chain or branched chain divalent hydrocarbon group; (n) is 1 or 2; W is H, carboxy alkyl or alkoxycarbonyl alkyl except a case in which all of W are H) and a salt thereof. EXAMPLE:2-(p-Nitrobenzyl)-1,4,7,10,13-pentaazacylopentadecane. USE:The bifunctional large cyclic chelate ligand can rapidly form strong chelate complexes with metal ions, the chelate complexes being utilized as e.g. contract agents for image diagnosis in the fields of medical diagnosis and treatment. PREPARATION:A compound of formula III (Y<1> is group of formula IV) is condensed with a compound of formula V (W<1> is carboxyalkyl, etc.,) in the presence of a base to prepare the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a novel bifunctional macrocyclic chelate ligand and a method for producing the same.

A bifunctional chelate ligand is a substance that has a chelate moiety with a metal ion and a bonding group with a biological substance such as a protein such as an antibody or a biological substance such as a saccharide in one molecule.

For example, in the fields of medical diagnosis and treatment, such bifunctional KEL-1-ligands bind antibodies with metal ions used in diagnosis and treatment, are administered to a living body, and are used to bind antibodies to antigens. It is used to concentrate metal ions at a target site using force. The present invention relates to a novel bifunctional chelating ligand that is extremely useful for use in such a purpose, and a method for producing the same.

<Prior art and problems to be solved by the invention> With the recent development of cell fusion methods, it has become relatively easy to obtain specific antibodies against various biologically related substances. Therefore, attempts have been made to use γ-cameras in diagnosing cancer and other diseases by binding and administering γ-ray emitting radioactive metals such as 111 99n In and IC to such specific antibodies. Attempts have been made to utilize nuclear magnetic resonance imaging (FIR) as a contrast agent for diagnosis by conjugating and administering G(l).
For example, The Journal of Nuclear Medicine (J, Nuc fear!-1edicine,
26.488 f1985)), International Journal of Cancer, (Int, J.

Cancer, 2.126 (1988)]6
90 67 186 This specific antibody also contains Y, Cu, Re18
8 211 212 The binding deviation of α- or β-ray emitting nuclides such as Re, A↑, and Bi can provide an effective means for treating various diseases, especially cancer [for example, Cancer Research (
Cancer Res, 48.3270 (1988)
), The Journal of Nuclear Medicine 7 (J, Nuclear t4edicine, 2
6.503 (1985))].

Conventionally, as a method of binding such antibodies and metals,
Ethylene thiamine mince 1 to 1, acid (EDTA
), a method of binding diethylenetriaminepentaacetic acid (DTPA) to antibodies and chelating metals, or EDT
A. A known method is to use a so-called bifunctional chelate ligand in which a bonding group with a biological material such as an inthiocyano group is introduced into DTPA.
．． 2772 (1986))] However, these ligands also do not have sufficient coordination power with metals, and after administration, the metals may be released or exchanged with metals present in the blood. However, it is not possible to sufficiently accumulate metal at the target site. In addition, when using EDTADTPA, a portion of the carboxylic acid moiety, which is a ligand for the metal, is used for binding to the antibody, so compared to the method using a bifunctional chelate ligand, the carboxylic acid moiety is a ligand for the metal. Not only does the coordination force of the antibody decrease, but the bond between the antibody and the CHIL-1 ligand is also unstable.

Therefore, bifunctional chelate ligands with stronger metal trapping ability are being investigated. Among them, macrocyclic polyamine derivatives are described by Donald et al. [Journal of American
Gemical Society (J, Am, Chem, S
oc, 1988. ．． 110.6266), U.S. Patent Box 4,678,667 Parker et al. [Journal of Chemical Society, Chemical Communication (J, Chem, Soc,
Chem.

Coun, 794, 797 (1989), European Patent No. 0238196] reported its excellent metal chelating ability.

However, as a result of separate studies by the present inventors, the above-mentioned macrocyclic chelate ligands have a strong ability to chelate with metals compared to EDTA, DTPA, etc., but they take a long time to form chelate complexes with metal ions. It was found that the method has disadvantages such as requiring

Therefore, it can be strongly and quickly removed from metal ions.
It is desired to develop bifunctional cle-1-ligands that form complexes.

Means for Solving the Problems In order to solve the drawbacks of the above-mentioned bifunctional chelate ligands, the present inventors attempted to form complexes between various chelate ligands and various metal ions. However, it was discovered that the bifunctional macrocyclic chelate ligand of the present invention rapidly and strongly forms a chelate complex with a metal ion, and the present invention was achieved.

SUMMARY OF THE INVENTION It is, therefore, an object of the present invention to provide bifunctional chelate ligands having superior metal A-layer ability and a method for producing them.

That is, the present invention provides macrocyclic polyamines represented by the following formulas [I], 2 or salts thereof, and macrocyclic polyamines [I] and bifunctional macrocyclics represented by the following formulas [■, A chelate ligand, a salt thereof, and an alkylating agent represented by the following formula [■, -W 1 ... [III] -1 are condensed in the presence of a base F, and then the necessary Deprotection and/or biocondensation of the functional group in the formula [n] as required, followed by deprotection as necessary and/or a bifunctional macrocyclic chelate ligand represented by the formula [I], and a method for producing a salt thereof, and macrocyclic polyamines represented by the above formula [n], characterized in that a macrocyclic polyamine dioxo derivative represented by the following formula [IV], 3 4 is treated with a reducing agent, and the method for producing its salt.

In the formulas [I], []I] and [IV], Z
represents a functional group capable of binding to a biological material or a functional group convertible thereto.

Such functional groups include, for example, a haloacetamide group: an isothiocyano group; an amino group; a maleimide group; a mercapto group; a 2-pyridyldithio group, and the like as functional groups capable of bonding with biological substances, and although some overlap, a nitro group; Amino group: Protected amino 5 can be mentioned as a convertible functional group.

In the formulas [■, [II], and [IV],
A represents a divalent hydrocarbon group having 1 to 10 carbon atoms,
For example, methylene group, ethylene group, propylene group, butylene group, pentylene group, hexylene group.

Divalent aromatic hydrocarbon groups represented by heptylene group, octylene group, nonylene group (representing an integer of 3 and linear or branched divalent hydrocarbons such as decylene group) can be mentioned.

In the above formulas [■], [■] and [1v], R1 represents a straight or branched chain divalent hydrocarbon group having 2 to 9 carbon atoms. For example, (v CH2+ 2, CHCH2CH3 6 H3 CH2C C 3 ('-C) 1 2-Zr-R-CHH3 CH2CH--CH2 + CH2 +3 H3 H2 CH3Cl-I 3 CH-C 2 CH3Cl- l3 CH3 CH2CCH2 CH3 CH-CH-CH- etc., but CH3CH3
CH3 +CH2+2, CHCH2, and CH2H3 are preferred.

■ Especially +3 In the formula [I], Y represents the structure N(-R2-N+. R2 in the formula % formula % is the same as the definition of R1 above, or R1 and R2 may be the same or different. Also, n represents 1 or 2.

In addition, in the above formula [I], the partial structure of -R1-YRl has the above formulas [II] and [IV] with respect to the center of Y.
It is preferable from the viewpoint of manufacturing that the partial structure of "Nioi" (-R1-Yl-R1) is a bilaterally symmetrical structure with respect to the center of Yl.

In the above formula [I], W may be the same or different and represents a hydrogen atom, a carboxydialkyl group, or an alkoxycarbonylalkyl group, except when all are hydrogen atoms.

An example of a non-hydrogen atom is a carboxymethyl group.

2-carboxyethyl group, 1-carboxyethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, 5-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group, 1-dicarbonylethyl group, benzyloxy Examples include carbonylmethyl group and benzyloxycarbonylethyl group.

In the above formula [11[], X represents a halogen atom or an activated derivative of alcohol. For example, an iodine atom,
Examples include a bromine atom, a chlorine atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, and a p-toluenesulfonyloxy group.

In the above formula []1[], W1 represents a group obtained by removing a hydrogen atom from the above definition of W.

Examples of the salts of the above formulas [I] and [II] include hydrofluoride, hydrochloride, and hydrobromide.

Examples include hydroiodide, acetate, trifluoroacetate, hydrofluoride, fumarate, sulfate, etc.
It is not limited to this.

The bifunctional macrocyclic ligand represented by the above formula [n] is a macrocyclic polyamine represented by the above formula [n] or a salt thereof, in a proportion of 2 to 30 times the mole of the base. In the presence of the alkalizing agent 5 to 20 represented by the above formula [■]
The compound is reacted with twice the molar amount, followed by deprotection and/or modification as necessary by biological condensation of the functional group defined as Z in the formula [nl, followed by necessary conversion.

The base used is potassium hydroxide, I-hydroxide,
Examples include inorganic bases such as carbonate, potassium carbonate, sodium carbonate, and cesium carbonate, and amine bases such as 1-ethylaminediazapine crownecene, pyridine, pyrrolidine, piperidine, and morpoline. Particularly preferred are potassium hydroxide, potassium carbonate, and cesium carbonate. The reaction temperature is -40 to ioo'c, particularly preferably W in the alkylating agent represented by the above formula 1]
0 to 90°C for carboxyalkyl groups, 0 to 50°C for alkoxycarbonylalkyl groups
A temperature range of approximately The reaction time varies depending on the reaction temperature, but is about 20 minutes to 3 days. The solvent used is one that does not react with the reaction reagent, such as water,
N,N-dimethylformamide, N,N dimethylacetamide, dimethyl sulfoxide, ethyl acetate, dichlorofuran, methanol, ethanol, Improvil alcohol, dimethoxyethane, dioxane, chloroform, methylene chloride, benzene, toluene, etc. alone, Mention may be made of mixed or biphasic solvents. In particular, in the alkylating agent represented by the above formula [1[I], when Wl is a carboxyalkyl group, a mixed solvent of water and ethanol or a two-phase solvent of water and l-luene is preferable, and when Wl is an alkoxycarbonylalkyl group, is preferably N,N-dimethylformamide, methanol, ethanol, or tetrahydrofuran.

When W is an alkoxycarbonylalkyl group in the bifunctional macrocyclic chelate ligand represented by the above formula [I], it may be hydrolyzed in the presence of 5 to 30 times the molar base or acid as necessary. By doing so, in the bifunctional macrocyclic chelate ligand represented by the above formula [I], W can be deprotected to a carboxyalkyl group. The base or acid used is sodium hydroxide monopotassium hydroxide,
Examples include sodium carbonate, potassium carbonate 1 ammonia, hydrochloric acid, and acetic acid.

Particularly preferred are sodium hydroxide, ammonia, and hydrochloric acid.

The reaction temperature is -40 to 100°C, particularly preferably 0 to 8°C.
A temperature range of about 0'C is employed. The reaction time varies depending on the reaction temperature, but is about 30 minutes to 1 day. The solvent used is one that does not react with the reaction reagent, and examples thereof include water, methanol, ethanol, N,N-dimethylformamide, dioxane, dimethyl sulfoxide, and the like alone or in combination. Particularly preferred are mixed solvents of water and methanol, and water and ethanol.

In the bifunctional macrocyclic chelate ligand represented by the above formula [I], when Z is a functional group that can be converted into a functional group that can bind to a biological material, a functional group that can bind to a biological material as necessary. can be converted to . Examples of such functional group conversion include converting a nitro group to an amino group, a cyano group to an aminomethyl group, an amino group to a haloacetamide group, an amino group to an isodiocyano group, and an amine group to a maleimide group. For example, from 21 to 2 groups to amino groups, from amino groups to haloacetate 1
-Amide group The following conditions may be used for functional group conversion from an amino group to an inthiocyano group.

Conversion from a nitro group to an amine group includes heterogeneous catalytic hydrogenation of a nitro compound as a substrate, reduction with metals and metal salts, reduction with metal hydrogen compounds, etc., but heterogeneous catalytic hydrogenation is particularly preferred. The catalyst used in this case is preferably 0.01 to 0.1 mole of 5 to 10% palladium-attached activated carbon or platinum (IV) oxide. The reaction temperature is from -40 to 200°C and the reaction pressure is from normal to 250 atm.

The reaction time varies depending on the reaction conditions, but is about 20 minutes to 1 day. The reaction solvent used is water, methanol, ethyl acetate, etc., and a solvent that dissolves the substrate is used.

Conversion from an amino group to a haloacetamide group can be carried out by reacting the amine serving as a substrate with 1 to 10 times the mole of activated tertiary ester of octopus acetic acid, haloacetyl halide, or the like. Activated esters of octoacetic acid include valanitrophenyl ester of iodoacetic acid or bromoacetic acid;
Examples of the haloacetyl halide include N-hydrohescissuccinimide ester and N-droxyphthalimide ester, and examples of the haloacetyl halide include iodoacetyl chloride, iodoacetyl bromide, bromoacetyl chloride, and bromoacetyl bromide. Reaction temperature is -40~100°
C1 is particularly preferably in the temperature range of -20 to 50°C. The reaction time varies depending on the reaction temperature, but is about 20 minutes to 3 days. The reaction solvents used are water, NN-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, dino 1-
Examples include xyethane, chloroform, and methylene chloride, with water, N,N dimethylformamide, and dimethyl sulfoxide being particularly preferred.

The conversion of an amino group to an inthiocyano group includes a reaction between an amine serving as a substrate and a solution of 1 to 5 times the mole of thiophosgene in 4 chloroform. The reaction temperature is in the range of -40 to 100°C, particularly preferably in the range of -20 to 50°C. The reaction time varies depending on the reaction temperature, but is approximately 5 minutes to 3 hours. The reaction solvent used is water,
Examples include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, methanol, ethanol, dimethoxyethane, chloroform, methylene chloride, etc. Water, N,N-dimethylformamide, and dimethylsulfoxide are particularly preferred.

The bifunctional macrocyclic chelate ligand obtained after such operations can be subjected to extraction, silica gel column chromatography, ion exchange chromatography, high performance liquid chromatography, centrifugal liquid-liquid partition chromatography, l-claffy, recrystallization. It can be isolated by appropriately selecting and applying common operations such as , distillation, etc., and performing them in combination.

The obtained bifunctional macrocyclic chelate ligand can be converted into a salt as described above by a known method, if desired.

5 The macrocyclic polyamines represented by the formula [II] can be obtained by reducing the macrocyclic polyamine dioxo derivative represented by the formula [IV].

Examples of the reducing agent include diphorane and sodium bis(2-methoxyethoxy)aluminum hydride, with diborane being particularly preferred. When diborane is used as a reducing agent, it is preferable to use 5 to 50 times the molar amount of phoran-tetrahydrofuran complex to the substrate, and the reaction temperature is about -20 to 20°C when adding the reducing agent dropwise, and then about 20 to 20°C. 3
A temperature range of about 0 to 100°C was adopted, and the reaction time was 3
It takes about 1 day. The reaction is carried out in the presence of an organic medium, and the medium used is an organic medium that does not react with the reaction reagent. Examples of such a medium include tetrahydrofuran, diethyl ether, dimethoxyethane, n-hexane, etc., and tetrahydrofuran is particularly preferred.

The macrocyclic polyamines obtained after such operations are extracted,
Silica gel column chromatography 1 to graphic ion exchange chromatography, high performance liquid chromatography 6 Isolation by appropriately selecting and applying ordinary operations such as chromatography, centrifugal liquid-liquid partition chromatography, recrystallization, and distillation. I can do it.

The obtained macrocyclic polyamines can be converted into salts as described above by known methods, if desired.

It should be noted that the macrocyclic polyamine dioxo derivative represented by the above formula [1v] may be synthesized by any method.
No. 50566) It can be synthesized by the following method. That is, amino acid derivative [1] and acetic acid derivative [2]
It can be synthesized by reacting 1 to obtain an iminodiacetic acid derivative [3], and then condensing this with polyamines [4].

XCH2C07R [2] [Month [3] [IV] 7 The bifunctional macrocyclic chelate ligand and its salt obtained by the present invention are new compounds that have not been described in the literature, and can rapidly and strongly interact with various metal ions. can form chelate complexes.

Examples of metal atoms that can form complexes include iso1helium (Y), indium (In), palladium (Pd), and technetium (Tc).
, transition metal ions such as rhenium (Re), copper (Cu), and lanthanide metal ions such as samarium (Sm), europium (Eu), and cadrinium (Gd). isn't it.

Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to these.

<Example 1> It was found that the complex formation rate was significantly faster with the ligand of 6 (Entry 5). In particular, the ligand having 6 nitrogen atoms (EntrV5) has a larger complex formation constant and a much shorter complex formation time than the Ent'ry1 ligand, which is conventionally considered to have the strongest coordination force. The bifunctional macrocyclic key-1-ligand of the present invention, in which a functional group capable of binding to biological substances is introduced into a complex ligand, has a weak coordination force and takes time to form a complex. It is possible to overcome the drawbacks of conventional ligands, such as, and is very useful for the treatment of various diseases, especially cancer.

The present inventors first synthesized several types of macrocyclic chelate ligands that are relatively easy to synthesize, and measured the rate of complex formation between them and various metal ions. Table 1 shows the results when yttrium ion (YB2) was used as the metal ion. As a result, the number of nitrogen atoms was 5 (Entry 4) or 90 compared to the ligand with 4 nitrogen atoms (Entry 1 to 3). ,2
5°C).

*1) Calculated from the time it takes for pI to stabilize after dropping the base.

*2) Measured values by Parker et al. [Journal of Chemical Society, xnication (J
, Chem, Soc, , Chem, Comm
Un, 797 (1989))].

1 3-(p-nitropencyl) -1,,1,7,10,
13 Pentaazacyclopentadecane-2,6-decane 6
．． 43 g (171111IIOl) was suspended in 200 ml of dry tetrahydrofuran under a nitrogen atmosphere, and after cooling with water, a solution of poran-tetrahydrofuran complex in tetrahydrofuran (I M , 300 ml +' 30011
111101) was added dropwise. After refluxing for 12 hours, the reaction mixture was cooled with ice, and 50 ml of water was added thereto, followed by 50 ml of 6N hydrochloric acid.
1 was added slowly. After distilling off the solvent, Tetodorofuran, under normal pressure, the reaction mixture was concentrated under reduced pressure while azeotropically distilling with methanol. 100 ml of water was added to the residue, washed with ether twice, and then concentrated. The residue was treated with ion exchange chroma 1-Graphie (Dowex 1-X8), the H20 eluted portion was collected, and the solvent was distilled off. The residue was recrystallized from acetonitrile to obtain 2.28 g of 2-(p-21-lovenzyl)-1,4,7°10.13-pentaazacyclopentadecane.
I got it. After concentrating the recrystallized solution, it was subjected to silica gel chromatography (ClICl3:HeoH:NH40H=
2-(p
Obtain 2.03 g of 1.4.7.10.13-pentaazacyclopentadecane (nitrobenzyl). Total 4.31
g (12,3nunol, yield 72%).

The physical property values of this compound are as follows.

'HNMR (CDCl2, δppn+); 1.8
1 (br, S, 5N), 2.25-3.12 (m,
21N).

7.34 (d, 2H, J=9Hz), 8.13 (d,
2H,J,=9Hz)・JR(K3r disc,
Cl1l-1) ;3215, 2890.2810.1
605.1595.1520゜1455, 1450.1
345.1130 1120m p: 126.5-127.5°C 3.FD-MS.

I/e351 [H 10 Old 10 Detection <Example 3> Pentaazacyclooctadecane 4 3-(p-nitrobenzyl) -1,4,7,10,1
6.32 g (15 nnol) of 3,16 hexaazacyclooctadecane-2,6-decane was dried in a nitrogen atmosphere, suspended in 200 ml of dolofuran, and after cooling with water,
Tetrahydrofuran solution of borane-tetrahydrofuran complex (IM, 300 ml, 3001011
101) was added dropwise. After refluxing for 12 hours, the reaction mixture was cooled with ice, and 50 ml of water and then 50 ml of 6N hydrochloric acid were slowly added thereto. After the solvent tetrahydrofuran was distilled off under normal pressure, the reaction mixture was concentrated under reduced pressure while azeotropically distilling with methanol. Add 100 ml of water to the residue, wash with ether, and then concentrate.

The residue was subjected to ion exchange chromatography (Dowex
1-X8), the H20 eluted portion was collected, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (CHCl3:HeoH:N)+40H=100
12;2-6:3:1), and the obtained amorphous solid was recrystallized from acetonitrile to obtain 2-(p
-nitrobenzyl)-1,4,7,1o, 13.16-
Hexaazacyclooctazocane 3.84g (9,76
1t1mOl, 65%) was obtained.

The physical property values of this compound are as follows.

“HNMR (CDCl2, δ1)I)In);
1.95 (br, S, 6H), 2.58-J3. l
5 (ni, 25H) 7.34 (d, 2H, J = 8.6H
1), 8°13 (d, 2N, J=8.8Hz)-IR
(Br disc, am-') ;3210,2
900.2820.1660.1605.1595゜1
515, 1430.1345.11155・mp: 142.5-143・FD MS.

! 1/e Detection Example 4 Synthesis of cyclopentadecane 2-(p-nitrobenzyl)-1,4,7,10,13
Pentaazacyclopentadecane 175■ (0.5 mmo
1) in 20 ml of N,N-dimethylformamide, and 0.62 g (4 ml) of methyl bromoacetate was added to 3 servings.
, 1.38 g (1011101 L) of potassium carbonate was added under nitrogen atmosphere.

Stirred at room temperature for 3.5 hours. After the reaction, the potassium carbonate was separated, water was added to the tear fluid, and the mixture was extracted with ethyl acetate.

The organic layer was washed with water, dried and concentrated, and the residue was purified with silica talc 0.
Futogura 7 E (C) ICI, : Heoll
=100:1).

Then, medium pressure preparative chromatography (CH2C1°:H
2-(p-nitrobenzyl)-1,4,7,10,13-pentaasa-1
,4,7,10,13pentakis(methoxycarbonylmethyl)cyclopentadecane 164■(0,23111
10+, yield 46%).

The physical property values of this compound are as follows.

'HNMR (CDCl2, δppn+); 2.5
0-3.00 (m, 21H), 3.34fS, 4H
).

3.40 (S, 6tl), 3.65 (S, 6+1),
3.66 (S, 3 old.

3.68 (S, 611), 7.44 (d, 21LJ=
8.8tlz).

8.13(d2+1.J=8.8NZ)・TR(n
eai, cm-') ;2960 2850 17
55 1740 1720 16057 595 515 430 340 ・FD-MS.

+n/e [10 detection <Example 5> 几2- (p-2) 7 jills to o) -1, 4, 7, 10,
1316 hexaasacyclooctade 197+ng
(0,5 nuno l) was dissolved in 10 ml of N,N-din-1-luporumamide, and 0.48 g of potassium carbonate (3,5111 Eol
) Then 0.92 g of methyl bromoacetate (6mm0l
) and stirred at room temperature under nitrogen atmosphere for 3.5 hours.

After the reaction, the potassium carbonate was removed from the furnace, water was added to the furnace liquid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated, and the residue was purified with Silica Gelc L17 Togra 7 E (CIICh
: HeoHloo:1-50:1) then medium pressure preparative chromatography (CH2Ct2:He0H=75:
1), purified by 2-(p21~lohenzil)-1
4,7,1,0,13,16-hexaasa-1,4,7
,10,13,16-hexakis(methoxycarbonylmethyl)cyclooctadecane 131■(0,159mm
ol, yield 32%).

The physical property values of this compound are as follows.

11(-NMR(CD, C13, δppm);2.
20-3.03 (n+, 25H), 3.35 (S,
4H) 3, l1OfS, 611), 3.65fS, 9
Old, 3.68 (S, 9H) 7.43id 211 J
=8.8t(z), 8.13(d, 21iJ=8.6
Hz) I R, (neat, am-') 2960, 2850 1755.1745.1735□
16051595 1515 1430 13403 f/e825 [1 dimension detection <Example 6> Synthesis of oxymethyl)cyclopentadecane 2-(p-2I
・Lobenzyl) -1,4,7,10,13pentaaza-1,4,7,10,13-pentakis(methoxycarbonylmethyl)cyclopentadecane 80.0 mg (0,
113 mmol) was dissolved in 5 ml of methanol, and 1.2 ml of 2N 1-lium hydroxide (2.4 mt
ool) was added thereto, and the mixture was stirred at room temperature for 8 hours. After the reaction, hydrochloric acid was added to bring the pH of the reaction solution to about 1, and the mixture was concentrated, and the residue was applied to a 5OBH type ion exchange column. First, elute with H2O, take an acidic fraction, and then elute with 2N ammonia water. Concentrate this fraction.
,10,13-pentaaza-1,4,7,10,13-
Pentakis(carboxymethyl)cyclopentadecane 6
9.1 mg (0.108 mlO yield 96%) was obtained.

The physical properties of this compound are as follows.

1111-1-N, (C20, δppm); 2.7
0-4.50 (m 31H) 7.48 (d, 2H,
J=8.8tlz).

8.15(d, 2H, J=8.6Hz)-IR(nii
, am-') ; 3425 1590 1520 1400 1345
1110・mp; > 170°C (decomposition); S
IMS; m/e 641 [8]÷Detection〈
Example 7> 2-(P-nitrobenzyl)-1,4,7,10,1
3,161I1.1 hair -1.47101316-hex carboxymethyl)cycloocta-dicane 42-(p-nitrobenzyl)-1,4,7,10,,13,16 hexaazor 1, 4.7 .10.13.16-hexakis(methoxycarbonylmethyl)cyclooctadecane 11
5 rag (0,14011111101) was dissolved in 5 ml of methanol, 0.84 ml (1,71111 Ol) of 2N sodium hydroxide was added thereto, and the mixture was stirred at room temperature for 4 hours. After the reaction, hydrochloric acid was added to bring the pH of the reaction solution to about 1, and the mixture was concentrated, and the residue was applied to a 503H type ion exchange column. First, elute with H2O, take the acidic fraction, then elute with 2N ammonia water, concentrate this fraction,
,16-hexaaza-1,4,7,10,13,16-
Hexakis(carboxymethyl)cyclooctadecane 8
4.1 mg (0,1131111101°Yield 81%
).

The physical property values of this compound are as follows.

LH-NMR ([)2 0. δppm)
;1.95-3. '95hn, 35tl), 7
．． 45 (d, 211.J=8.4Hz) 8.14 (d,
2H, J=8.4tlz)・IR(KBr, am
-” ) ;3420, 1590.1515.1395
．． 1340.10109O-; >185°C (decomposition) -S I M S ;
l] + Detection <Example 8> 3 2-(p-nitrobenzyl)-1,4,7,10,13
Pentaasa-1,4,7,10,13-pentakis(carboxymethyl)cyclopentadecane 226■(0,3
53n+n+ol) was dissolved in 5 ml of water, and the l)H was adjusted to about 10 with 2N hydroxide. 55 μm of 10% palladium-attached activated carbon was added to this, and the mixture was stirred at normal pressure and room temperature under a hydrogen atmosphere for 5 hours. After the reaction, the palladium-attached activated carbon was removed and the pH was adjusted to about 1.2 with 5N hydrochloric acid. After concentration, the residue was applied to an ion exchange column of type -503)1. First, elute with H2O, take the acidic fraction, and then
Elute with 2N aqueous ammonia, concentrate this fraction,
-(p-aminobenzyl)-147,10,13-pentaaza-1,,l,7,10.13-penta4kis(carboxymethyl)cyclopentadecane 161
mg (0,261111O1, yield 75%) was obtained.

The physical property values of this compound are as follows.

IH-NMR (020, δ ppm); 2
．． 16-4.16 (m, 31H), 6.83 (d, 2N
, J=8.1Hz).

7.09(d,2H,J=8.1H2)-IR(toBr
, an-1); 3425 1640, 1635.1620.1610.
15901520 1400, 1330, mp:〉225°C (decomposition)

Claims (1)

[Claims] 1. The following formula [I], ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[I
] In the formula, Z represents a functional group capable of bonding with a biological material or a functional group convertible thereto, and A represents a 2-carbon group having 1 to 10 carbon atoms.
R^1 representing a valent hydrocarbon group represents a linear or branched divalent hydrocarbon group having 2 to 9 carbon atoms. Y is represented by the structure ▼There are mathematical formulas, chemical formulas, tables, etc.▼. Here, R^2 represents a linear or branched divalent hydrocarbon group having 2 to 9 carbon atoms, and n is 1 or 2. W may be the same or different from each other, and hydrogen atoms,
Represents a carboxyalkyl group or an alkoxycarbonylalkyl group, excluding cases where all hydrogen atoms are present. A bifunctional macrocyclic chelate ligand represented by: and a salt thereof. 2. The bifunctional macrocyclic chelate ligand according to claim 1, wherein in the formula [I], Z is a nitro group, an amino group, a protected amino group, a cyano group, an isothiocyano group, or a haloacetamide group. , and its salt. 3. In the above formula [I], A is a methylene group, an ethylene group,
Claim 1 which is a propylene group or ▲ has a mathematical formula, chemical formula, table, etc. ▼ (in the formula, m represents an integer from 0 to 3)
or the bifunctional macrocyclic chelate ligand according to 2, and a salt thereof. 4. In the above formula [I], R^1 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or a hydrocarbon having 1 to 7 carbon atoms in any position thereof The bifunctional macrocyclic chelate ligand according to any one of claims 1 to 3, which is a divalent hydrocarbon group having 1 to 2 groups, and a salt thereof. 5. In the above formula [I], Y is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas, tables, etc. etc.▼ (In the formula, W is the same as the definition of the above formula [I].) or a divalent hydrocarbon group having 1 to 4 hydrocarbon groups having 1 to 7 carbon atoms at any position thereof. The bifunctional macrocyclic chelate ligand according to any one of claims 1 to 4, and a salt thereof. 6. In the above formula [I], W may be the same or different from each other, a hydrogen atom, a carboxymethyl group, a carboxyethyl group, a methoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylethyl group, benzyloxycarbonylmethyl group or benzyloxycarbonylethyl group,
The bifunctional macrocyclic chelate ligand according to any one of claims 1 to 5, and a salt thereof, except when all hydrogen atoms are present. 7. The following formula [II], ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[II] [In the formula, Z, A, and R^1 are the same as N as defined in the above formula [I]. Y^1 is represented by the structure ▲There are mathematical formulas, chemical formulas, tables, etc.▼. Here, R^2, n is the same as the definition of the above formula [I]. ] Macrocyclic polyamines represented by these, and salts thereof. 8. The macrocyclic polyamines and salts thereof according to claim 7, wherein Z in the formula [II] is a nitro group; an amino group; a protected amino group; a cyano group; an isothiocyano group; or a haloacetamide group. 9. In the formula [II], A is a methylene group, ethylene group, propylene group, or ▲a mathematical formula, a chemical formula, a table, etc.▼ (in the formula, m represents an integer from 0 to 3), Claim 7
or the macrocyclic polyamines described in 8, and salts thereof. 10. In the above formula [II], R^1 is ▲There is a mathematical formula, chemical formula, table, etc.▼, ▲There is a mathematical formula, chemical formula, table, etc.▼ or a hydrocarbon having 1 to 7 carbon atoms in any position thereof The macrocyclic polyamine according to any one of claims 7 to 9, which is a divalent hydrocarbon group having 1 to 2 groups, and a salt thereof. 11. In the above formula [II], Y^1 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas , tables, etc.▼ or a divalent hydrocarbon group having 1 to 4 hydrocarbon groups having 1 to 7 carbon atoms at any position thereof.Claim 7
Macrocyclic polyamines according to any one of 10 to 10,
and its salt. 12. Macrocyclic polyamines represented by the following formula [II],
or a salt thereof, and the following formula [III], X-W^1...[III] [wherein, Represents an alkoxycarbonylalkyl group. ] The alkylating agent represented by is condensed in the presence of a base, and then, if necessary, deprotected and/or the functional group Z in the formula [II] is converted into a functional group that can react with biological substances. A method for producing a bifunctional macrocyclic chelate ligand represented by the formula [I] and a salt thereof, characterized in that: 13. The following formula [IV], ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[IV] [In the formula, Z, A, and R^1 are the same as the definitions of the above formula [I]. Y^1 is the same as the definition of formula [II] above. A method for producing macrocyclic polyamines represented by formula [II] and salts thereof, which comprises treating a macrocyclic polyamine dioxo derivative represented by formula [II] with a reducing agent.