JPH03112969A - Producing intermediate of bifunctional chelate ligand and production thereof - Google Patents

Abstract

NEW MATERIAL:An imino diacetic acid derivative expressed by formula l and salt of said derivative (Z is functional group bondable with biosubstance functional group convertible to said biosubstance; A is 1-10C bifunctional hydrocarbon group, R is 1-8C hydrocarbon group). EXAMPLE:An N-[alpha-(p-nitrobenzyl)-methoxycarbonyl methyl]-N-methoxycarbonyl methylamine. USE:Used in medical diagnosis or remedy field. Used as raw material of synthesis of large ring polyamine dioxo derivative expressed by formula II and salt of said derivative [R<2> is 2-9C bifunctional hydrocarbon group; Y is expressed by formula III (R<2>=R<1>; n is 0.2)] as a novel substance useful for efficiently producing bifunctional large ring chelate ligand making metal to strong chelate and having bonding group to protein such as carrier or bio-relating substance such as saccharides. PREPARATION:Amino acid derivative expressed by formula IV or salt of said derivative is reacted with acetic acid derivative expressed by formula V (X is halogen) in a solvent in the presence of base to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to intermediates for the production of bifunctional chelate ligands and methods for their production. More specifically, we will efficiently produce so-called bifunctional chelating ligands that strongly chelate metals and have bonding groups with proteins such as antibodies and biologically related substances such as sugars, which are used in the fields of medical diagnosis and treatment. The present invention relates to manufacturing intermediates and methods for manufacturing them.

<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, such a specific antibody as 1111n, ""Tc
Attempts have been made to use γ-cameras to diagnose cancer and other diseases by combining and administering γ-ray-emitting radioactive metals, and by combining and administering Gd to nuclear magnetic resonance. Attempts have been made to use it as a contrast agent for image diagnosis using
arMedicine, 26.488 (1985)
), International Journal of Cancer (IΩt, J.

Cancer, 2.126 (1988)].

In addition, this specific antibody contains 90Y, 67C, 186Re.
.

Combining α- or β-ray emitting nuclides such as 188R, 211At, and 21213i can provide an effective means for treating various diseases, especially cancer [for example, Cancer Research, 48.3
270+1988)), The Journal of Nuclear Medicine 7 (J, Nuclear Me
dicine, 26.503+1985))].

Conventionally, as a method of binding such antibodies and metals,
A method of binding ethylenediaminetetraacetic acid (EDTA) or diethylenetriaminepentaacetic acid (DTPA) to an antibody to chelate a metal, or a so-called bifunctional chelate coordination method in which a bonding group with a biological material such as an inthiocyano group is introduced into EDTA or DTPA. It is known that a method using inorganic chemistry [Inorganic Chemistry]
nicChemistry, 25.2772 (19
86)) However, these ligands still do not have sufficient coordination power with the metal, and after administration, the metal may be liberated or exchanged with the metal present in the blood, making it difficult to achieve the intended purpose. It is not possible to accumulate metal in these areas. Also, ED
T.A.

When using DTPA, part of the carboxylic acid moiety that is the ligand for the metal is used for binding to the antibody, so compared to the method using a bifunctional chelate ligand, the ligand for the metal is less likely to bind to the antibody. Not only is the potential strength reduced, but the bond between the antibody and the chelate ligand is also unstable.

Therefore, research and development are being conducted on bifunctional chelate ligands that have stronger metal trapping ability. Among them, macrocyclic polyamine derivatives are described by Donald et al. [Journal of American Chemical Society (J, Am, Chem,
Soc, 1988.110.6266), U.S. Patent No. 4.678.667] and Parker et al.
Commun.

794, 797 +1989)), European Patent No. 0238
1961 reported its excellent metal chelating ability.

Incidentally, methods for synthesizing macrocyclic polyamine derivatives as described above have been reported by Donald et al. and Barker et al., but all of these methods have drawbacks such as long and complicated steps and poor total yields. .

Therefore, it is desired to provide a method for efficiently synthesizing macrocyclic polyamine derivatives as bifunctional chelate ligands.

Means for Solving the Problems As a result of intensive research into an efficient synthesis method for macrocyclic polyamine derivatives, the present inventors synthesized an iminodiacetic acid derivative and reacted it with polyamines to synthesize a bifunctional chelate compound. The present invention was achieved by discovering a route for efficiently synthesizing synthetic intermediates for various macrocyclic polyamine derivatives useful as ligands.

Therefore, an object of the present invention is to provide intermediates for producing bifunctional chelate ligands having excellent metal chelating ability and methods for producing them.

That is, the present invention provides an iminodiacetic acid derivative represented by the following formula [II] and its salt, a macrocyclic polyamine dioxo derivative represented by the following formula [II] and its salt, and the following formula [III] 9ryoC02R H2...[ III] [wherein Z, A, and R are the same as in the above formula [II]. A method for producing the above formula [II and a salt thereof, which is characterized in that an amino acid derivative represented by the following formula [IV] or a salt thereof is reacted with an acetic acid derivative represented by the following formula [IV] XCH2C02R [TV] in the presence of a base, and Iminodiacetic acid derivative [II and the following formula [V] R2N -R' -Y -R' -N R2... [V
] [In the formula, R1 and Y are the same as in the above formula [II]. ] The present invention relates to a method for producing the formula [II] and its salt, which is characterized by reacting the polyamines represented by the following formula [II].

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

For example, nitro group, cyano group, carboxyl group, hydroxyl group,
Examples include a formyl group, a carboxamide group, a halogen group, and a protected amino group, among which a nitro group, a cyano group, and a protected amine group are particularly preferred. These functional groups may be converted into macrocyclic polyamine dioxo derivatives according to the method of the present invention and then converted into functional groups capable of bonding with biological substances as appropriate. For example, a nitro group can be bonded to a biological material by leading to an amino group, an isothiocyano group, a haloacetamide group, or the like.

In the above formulas [I], [II and [III], A represents a divalent hydrocarbon group having 1 to 10 carbon atoms, such as a methylene group, an ethylene group, a propylene group, a butylene group,
Straight chain or branched chain divalent hydrocarbon groups such as bentylene group, hexylene group, hexylene group, octylene group, nonylene group, decylene group and Examples include divalent aromatic hydrocarbon groups represented by (representing).

In the above formulas [I], [III] and [IV], R represents a hydrocarbon group having 1 to 8 carbon atoms. For example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, isopropyl group, 5ec-butyl group, tert-butyl group, isobutyl group, isopentyl group, benzyl group, phenethyl group, etc. Among them, methyl group and ethyl group are preferred.

In the above formulas [n] and [V], R1 has 2 to 9 carbon atoms
linear or branched divalent hydrocarbon groups H3 CH3 CH3 CH3 +cH2+2, -CH CH3 CH2-.

MoCR2+3 is preferred.

In the above formulas [II and [V], Y has a structure represented by -N(-R2-N+), and R2 is 1(H). A hydrocarbon group, n represents O mana 1 mana 2. For example, as Y, N- 1 ( -N-eCH2+2 N- HH 0 formula N+CH2+3 N- HH H3 NmoCR2+2 N + CH2+ 2 NHHH -N+CH2)3 -N+CHz+3 N-HHH -N(-CHz+2 N- HH N+CHz+3N- HH In addition, in the above formulas [II] and [V], R1-Y
It is preferable for the part i structure of -R4- to have a bilaterally symmetrical structure with respect to the center of Y from the viewpoint of manufacturing.

Examples of the salts of the above formulas [I], [II] and [III] include hydrofluoride, hydrochloride, hydrobromide,
Examples include, but are not limited to, hydroiodide, acetate, trifluoroacetate, hydrofluoride, fumarate, sulfate, and the like.

X in the above formula [■] is a halogen atom, and among them, a chlorine atom, a bromine atom, and an iodine atom are preferable.

The iminodiacetic acid derivative represented by the above formula [II] is prepared by adding the amino acid derivative represented by the above formula [III] or a salt thereof to the above formula [IV] in the presence of a base of 0.5 to 5 times the molar amount.
It is produced by reacting with 1 to 5 times the mole of an acetic acid derivative represented by Examples of the base used include amine bases such as triethylamine, diazabicycloundecene, pyridine, pyrrolidine, piperidine, and morpholine, and inorganic bases such as potassium carbonate and sodium carbonate, with triethylamine and potassium carbonate being particularly preferred. The reaction temperature is -40°C to 100°C, particularly preferably O
A temperature range of approximately 50° C. is employed. The reaction time varies depending on the reaction temperature, but is approximately 20 minutes to 10 hours. 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. Such media include N,N-dimethylformamide, N,N
-Dimethylacetamide, dimethylsulfoxide, ethyl acetate, tetrahydrofuran, methanol, ethanol, dimethoxyethane, dioxane, chloroform, methylene chloride, and the like. Particularly preferred are N,N-dimethylformamide, tetrahydrofuran, and methanol.

The iminodiacetic acid derivative obtained after such operation is extracted,
It can be isolated by appropriately selecting and applying conventional operations such as silica gel column chromatography, ion exchange chromatography, high performance liquid chromatography, centrifugal liquid-liquid partition chromatography, recrystallization, and distillation.

The obtained iminodiacetic acid derivative can be converted into a salt as described above by a known method, if desired.

The macrocyclic polyamine dioxo derivative represented by the above formula [II] is added in an amount of 0.5 to 3 equivalents, more preferably 0.8 to 1.0 equivalents, to the iminodiacetic acid derivative represented by the above formula [I].
It is produced by reacting 5 equivalents of polyamines represented by the above formula [V].

The reaction temperature is -40-150°C, particularly preferably 40-150°C.
A temperature range of about 00°C is adopted. The reaction time varies depending on the reaction temperature, but is about 3 to 20 days.

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. Such media include N,N-dimethylformamide, N,
Examples include N-dimethylacetamide, dimethylsulfoxide, ethyl acetate, tetrahydrofuran, methanol, ethanol, dimethoxyethane, dioxane, chloroform, methylene chloride, and the like. Particularly preferred are methanol and ethanol. The concentration of each reaction reagent is preferably 0.5M or less, more preferably about 0.05M.

The macrocyclic polyamine dioxo derivative obtained after such operations was subjected to extraction, silica gel column chromatography,
Isolation can be achieved by appropriately selecting and applying conventional operations such as ion exchange chromatography, high performance liquid chromatography, centrifugal liquid-liquid partition chromatography, recrystallization, and distillation.

The obtained macrocyclic polyamine dioxo derivative can be converted into a salt as described above by a known method, if desired.

The iminodiacetic acid derivative and its salt and the macrocyclic polyamine dioxo derivative and its salt of the present invention are new compounds that have not been described in any literature, and are useful as intermediates for the production of bifunctional chelate ligands. Furthermore, these manufacturing methods are also simpler and involve fewer steps than known methods.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to examples, and application examples of the present invention will be described, but the present invention is not limited to these.

<Example 1> Synthesis of p-nitrophenylalanine methyl ester hydrochloride (3
0,0g, 0.115 mol) was suspended in 250 ml of N,N-dimethylformamide, triethylamine (11.6 g, 0.115 mol) was added thereto, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was filtered to remove precipitates, the filtrate was concentrated under reduced pressure. The residue was dissolved in 250 ml of NN dimethylformamide, and methyl bromoacetate (35.2 g', 0.0 g) was added thereto under a nitrogen atmosphere.
23 mol), then triethylamine (23.2 g
, 0.23 mol) and stirred at room temperature for 1 hour.

After the reaction mixture was filtered to remove precipitates, the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and then with saturated brine, and then dried over anhydrous sodium sulfate. After filtration, N-[α-(p
-nitrobenzyl)-methoxycarbonylmethyl]-N
-Methoxycarbonylmethylamine (34.0g, 0
．． 115 mol, 100%) was obtained. This can be used as is for the next reaction, but it can be used for the next reaction by silica gel column chromatography (CH2CI2:MeOH=l
It is also possible to purify by OO: 1). Note that the yield when purification was performed was 92%.

The physical property values of this compound are as follows.

IH-NMR (CDCl2, δppm); 2.06
(s, IH) 3.03-3.17 (m, 2H)3.
40 (s, 2H), 3.48 (t, IH, J=7Hz
l.

3.70<5,6H), 7.40(d,2H,J・
9Hz18,15 (d, 2H, J=9H2).

IR(neat, cm-”); 3350 2970, 1755.1730.1610.
15201435, 1350.1110.101015
FD−; m/e 296 (M>”, 297 (M+H)+ detection) When methanol was used as the solvent for this reaction, the yield was 72%.

<Example 2> Synthesis of azacyclododecane-2,6 monodione N-[α-(p-nitrobenzyl)methoxycarbonylmethyl]=N-methoxycarbonylmethylamine (3
4.0g, 0.115mol) and diethylenetriamine (11.9g, 0.115mall) were dissolved in 2g of dry methanol and refluxed for 10 days under a nitrogen atmosphere.The reaction solution was concentrated to about 300ml and stirred at room temperature - day and night. 3-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane 2,6-dione (9.24 g, 27.6 mmol,
24%).

The physical property values of this compound are as follows.

'f(-NMR(D20/DCI, δppm1;3,
14-3.50 (m, 8H), 3.77 (
s, 2H) 4.11 (d, 2)1. J=8.5
Hz), 4.30-4.52 (m, IH)7, 5
2 (d, 2H, J=9Hz), 8.15 fd,
2H, J=9Hz).

I R (KBr disc, cr"); 3270,
3080.2950.1660.1640.1600゜1510, 1340.1140 1110.10104
5FD-; m/e 335 (M) +, 336 (M+H) + detection mp; 230°C (decomposition) <Example 3> N-[α-(p-nitrobenzyl)methoxycarbonylmethyl]-N -methoxycarbonylmethylamine<
24.3 g, 82 mmol) and triethylenetetramine (12.0 g, 82 mmol) in dry meta/-/[
/1.7 (J) and refluxed for 7 days under nitrogen atmosphere. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (CHCl3:MeOH:28
%NH3 water 100:7 1~100:12:2
). The obtained crystals were suspended in ethyl acetate, heated and stirred, and the crystals were collected to obtain 3-(p-nitrobenzyl)1.4,710.13-pentaazacyclopentadecane 2.6-sion (7.10 g, 18.8mm
ol, 23%) was obtained.

The physical property values of this compound are as follows.

'HNMR (CDCh, δppm); 1.50 (b
r, s 3H), 2.52-2.86 (m, 8H)
2.96-3.66 (m, 9) ri, 7.40 (d, 2
H, J=9H2) 7.42 (br, s, 2H), 8
．． 70 (d, 2H, J=9Hz) I R (KBr di
sc, am-') ;3300 2815 1660
1640, 1600.15101350 1130
1105° FD-MS; m/e 379 (M+H) + detection mp; 166-167°C <Application example of the present invention> The macrocyclic polyamine dioxo derivative obtained by the method of the present invention has various useful bifunctional properties. can lead to macrocyclic chelating ligands. For example, Donald et al. synthesized the following intermediate A using a method different from the present inventors and led to B.

[Journal of the American Chemical Society (J, Am.

Chem, 5oc1.1988.110.6266)
] According to the method of the present inventors, compound A can be easily synthesized. Further, the nitro group of compound B can be easily converted into a functional group capable of bonding to a biological material. As a reference example, a method for guiding the macrocyclic polyamine dioxo derivative obtained in Example 2 to compound B via compound A will be described below, but this does not limit the present invention.

Reference Example 1> 3-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-2,6-sion (6,70 g
.

20 mmol Il was suspended in 200 ml of dry tetrahydrofuran under a nitrogen atmosphere, and after cooling with water, a tetrahydrofuran solution of borane-tetrahydrofuran complex (IM) was added.

300 ml, 300 mmol) 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 is distilled off under normal pressure, the reaction mixture is concentrated under reduced pressure while azeotroping with methanol. 100 ml of water was added to the residue, washed with ether, and then concentrated.

The residue was subjected to ion exchange chromatography (Dowex 1
-X8), the H20 eluted portion was collected, and the solvent was distilled off. After purifying the residue using centrifugal liquid-liquid partition chromatography, the obtained crystals were recrystallized twice from acetonitrile to obtain 2-(p
-nitrobenzyl)-14,7,10-tetraazacyclododecane (4,47 g.

14.6 mmol, 73%) was obtained.

The physical property values of this compound are as follows.

"HNMR (CDCl2, δppm); 2.20 (
br, s, 4H1, 2j5-3.06 (m, 17H
)7,35 (d, 2)1. J=9Hz), 8.
14 (d, 2H, J=9Hz).

13C-NMR (CDCl2, δppm): 39.
985.44.604.46.266, 46.372.
46.57146.677, 50.214.50.64
1.56.541.123.496129.838.1
46.486.147.431゜FD-MS; m/e 308 (M+H) + detection TR (KBr disc, cm"); 3330,
2850.1595.1515.1460.1440.
1340° 1110, 1065 mp; 110-111°C <Reference Example 2> Bromoacetic acid (1.39 g, 10 mmol) in 15 ml of water
1 and cooled with water to 7M KO)I (2,86ml
．． 20m+nol) was added.

2-(p-nitrobenzyl)-1,47,
10-tetraazacyclododecane (0.62g, 2m
Add 20 ml of ethanol solution of mo I) and heat at 70°C.
Stir for 4.5 hours. The reaction mixture was adjusted to pH = 3.4 with 47% hydrobromic acid, the precipitate was collected, and
-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-N,N',N',N''-tetraacetic acid (0,57 g.

1.05 mmol, 52%) was obtained.

The physical property values of this compound are as follows.

"HNMR (D20/Na0D, 8ppm): 2.20
-4.10 (m, 25)! 1. 7.46(d 2H,
J=9)IZ).

8, 16 (d, 2H, ni 9H2) I R (KBr disc, am-'); 3430
, 3110.1680.1515.1455.1345
．． 1250° 1080° SIMS; m/e 540 (M+H) + detection mp; 215°C (decomposition)

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] [In the formula, Z is a functional group that can bond to a biological substance or a functional group that can be converted thereto. , A represents a divalent hydrocarbon group having 1 to 10 carbon atoms, and R represents a hydrocarbon group having 1 to 8 carbon atoms. ] Iminodiacetic acid derivative and its salt 2, the following formula [II] ▲ Numerical formulas, chemical formulas, tables, etc. are available▼... [II] [In the formula, Z and A are the same as the above formula [I]. R^1 represents a straight chain or branched chain divalent hydrocarbon group having 2 to 9 carbon atoms, and Y is represented by the structure ▲There are numerical 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 0, 1, or 2. Macrocyclic polyamine dioxo derivatives and salts thereof . The following formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[III] [In the formula, Z, A, and R are the same as the above formula [I]. An amino acid derivative or a salt thereof represented by the following formula [IV] XCH_2CO_2R...[IV] [wherein, X represents a halogen atom] R is the formula [ I
] Same as. ] A method for producing an iminodiacetic acid derivative represented by the formula [I] and a salt thereof, which comprises reacting the acetic acid derivative represented by the following in the presence of a base. 4. The iminodiacetic acid derivative [I] according to claim 1 and the following formula [V] H_2N-R^1-Y-R^1-NH_2...[V]
[In the formula, R^1 and Y are the same as in the above formula [II]. ] A method for producing a macrocyclic polyamine dioxo derivative represented by the formula [II] and a salt thereof, which comprises reacting the macrocyclic polyamine dioxo derivative represented by the formula [II] with a polyamine represented by the formula [II]. 5. The iminodiacetic acid derivative and its salt according to claim 1, wherein Z in the formula [I] is a nitro group, a cyano group, or a protected amino group. 6. Claim 1 or claim 1, wherein in the formula [I], A is a methylene group, an ethylene group, a propylene group, or ▲a mathematical formula, a chemical formula, a table, etc.▼ (in the formula, k represents 0 to 3) 5. The iminodiacetic acid derivative and its salt according to 5. 7. The iminodiacetic acid derivative and its salt according to claim 1, 5 or 6, wherein R in the formula [I] is a methyl group or an ethyl group. 8. The macrocyclic polyamine dioxo derivative and its salt according to claim 2, wherein Z in the formula [II] is a nitro group, a cyano group, or a protected amino group. 9. Claim 2 or claim 2, wherein in the formula [II], A is a methylene group, an ethylene group, a propylene group, or ▲a mathematical formula, a chemical formula, a table, etc.▼ (in the formula, k represents 0 to 3) 8. The macrocyclic polyamine dioxo derivative and its salt as described in 8. 10. In the above formula [II], R^1 is ▲ There is a mathematical formula, chemical formula, table, etc. ▼ or ▲ There is a mathematical formula, chemical formula, table, etc. ▼
10. The macrocyclic polyamine dioxo derivative and its salt according to claim 2, 8 or 9, which are ▲a mathematical formula, a chemical formula, a table, etc.▼. 11. In the above formula [II], Y is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲Mathematical formulas, chemical formulas, tables, etc. The macrocyclic polyamine dioxo derivative and its salt according to claim 2, 8, 9 or 10, which are ▼. 12. The method for producing iminodiacetic acid derivatives and salts thereof according to claim 3, wherein Z in the formula [III] and the formula [I] is a nitro group, a cyano group, or a protected amino group. 13. In the formula [III] and the formula [I], A is a methylene group, an ethylene group, a propylene group, or ▲a numerical formula, a chemical formula, a table, etc.▼(in the formula, k is 0
The method for producing iminodiacetic acid derivatives and salts thereof according to claim 3 or 12, wherein 14, the above formula [III], the above formula [IV] and the above formula [I
] The method for producing iminodiacetic acid derivatives and salts thereof according to claim 3, 12, or 13, wherein R is a methyl group or an ethyl group. 15. Claim 3 or 12 or 13 or 1, wherein in the formula [IV], X is a chlorine or bromine atom.
4. The method for producing the iminodiacetic acid derivative and its salt according to 4. 16. The method for producing macrocyclic polyamine dioxo derivatives and salts thereof according to claim 4, wherein Z in the formula [I] and the formula [II] is a nitro group, a cyano group, or a protected amino group. 17. In the above formula [I] and above formula [II], A is a methylene group, an ethylene group, a propylene group, or ▲a numerical formula, a chemical formula, a table, etc.▼ (in the formula, k represents 0 to 3) The method for producing macrocyclic polyamine dioxo derivatives and salts thereof according to claim 4 or 16. 18. The method for producing a macrocyclic polyamine dioxo derivative and a salt thereof according to claim 4, 16, or 17, wherein R in the formula [I] is a methyl group or an ethyl group. 19. In the formula [II] and the formula [V], R^1 is ▲
The macrocyclic polyamine according to claim 4 or 16 or 17 or 18, which has mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ Method for producing dioxo derivatives and salts thereof. 20. In the above formula [II] and the above formula [V], Y is ▲ There is a mathematical formula, chemical formula, table, etc. ▼ or ▲ There is a mathematical formula, chemical formula, table, etc. ▼ or ▲ There is a mathematical formula, chemical formula, table, etc. ▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼Claim 4 or 16 or 17 or 18 or 1
9. A method for producing a macrocyclic polyamine dioxo derivative and a salt thereof according to 9.