JPH02502820A - Substituted complexing agents, complexes and complex salts, their preparation and preparations containing them - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Substituted complexing agents, complexes and complex salts, their production methods and preparations containing them The present invention is characterized in the patent claims and aims to provide novel complexing agents, complexes and complexes. salts, drugs containing this compound, its use in diagnosis and therapy and this compound Issues related to manufacturing methods for products and drugs.

The use of complexing agents or Fi complexes or their salts in medicine has been known for a long time. Examples include: Complexing agents as stabilizers in pharmaceutical preparations, for the administration of poorly soluble ions (e.g. iron) complexes and their salts as auxiliary agents, heavy metals or their radioactive amounts of water elements. optionally with salts with inorganic and/or organic bases as antidotes for the detoxification of Complexing agents and complexes (especially calcium- or zinc-) and scintigraphic Radioactive isotopes for example 991! ITc (D) used as an assistant in nuclear medicine Complexing agents as agents are known.

VS Toy: / Country 4Li’F Publication Publication (DE-O3) No. 3401052 details In the book, new paramagnetic complex salts are presented as diagnostic agents, mainly as NMR-diagnostic agents. ing.

All previously known complexes and their salts have been shown to be tolerable and/or binding during their clinical use. There are problems with the selectivity and/or stability of The product derived from the complexing agent is These problems become more severe as more doses have to be administered. extraintestinal The per se useful use of heavy elements as components of the Rentodan contrast agent to be administered Previous attempts have been met with failure due to insufficient tolerability of compounds such as . Conventional nuclear spin tomography Paramagnetic substances have been proposed and tested for effective doses and animal experiments. The distance between the toxic doses is relatively narrow and/or this may result in little organ specificity and/or exhibits stability and/or contrast-enhancing effects and/or is poorly tolerated. be.

On the one hand, by ionic bonding to respective appropriate metals (see below) and on the other hand, by functional groups or is a non-toxic and as organ-specific macromolecule that can be used as a carrier molecule. These problems can be alleviated by the use of complexing agents that are attached by bonds to molecules. Previously, the method of elucidating at least part of the problem was only effective in a limited number of cases and rarely. Ta.

When the functional group of a complexing agent is used for the attachment of molecules to biological molecules, complex stability Physiologically unacceptable macromolecule-metal ion-complex The metal ion components capable of oxidation are liberated [Pike (C, H.

Patk) et al., J. Radioanal, Chem, vol. 57, p. 553 ( 1980), D. J* Hnaloevich et al., J. Nuel.

M@d, vol. 26, p. 503 (1985)].

On the other hand, this functional complexing agent, i.e. the desired metal one (other) functional group for the coordination bond of the macromolecule as well as one (other) functional group for the attachment of the macromolecule When using a complexing agent having C, F, Memnea) et al., Radioimmunoimaging and Radio Immunotherapy (Radioimmunoimming and Radio immt+noth*rapl*) 1983.185, Canadian patent (Cat+ mdisch@5patent) No. 1178951), a wide variety of Disadvantageous disadvantages arise, such as the low stability of the complex.

The multistep and difficult synthesis of the complex, the slight modification of the functional groups required for attachment to the macromolecule. risk of impurity with foreign metals during the synthesis of the complexing agent, low lipophilicity (L Only limited reactivity potential of complexing agents based on ipophili*), reduced yields and additional purification steps coupled with necessary intermediate blocking of the functional groups of the complexing agent (e.g. iron - phenolic hydroxy groups as complexes or as methyl ethers), high Need for purifying solvents and work equipment.

Therefore, for a variety of purposes, as many functional groups as possible are suitable for attachment to macromolecules. stable, well soluble and well selective, but identical There is a need for well-available complex compounds with better tolerability. follow The present invention aims to make these compounds and drugs freely available and as simple as possible. The challenge is simply to create a manufacturing method.

This problem is solved by the present invention.

- Functionalized aminopolycarginic acid anion and atomic number 21-29.31 , 32.37-39. One or several central atoms of the elements 42-44 or 57-83 and optionally one or several cations of inorganic and/or organic bases or amino acids. Compounds consisting of ions are used as diagnostic agents and radiation. It has been found to be surprisingly eminently suitable for the production of therapeutic agents.

The compounds according to the invention are described by the general formula l: [where n and m are each the number 0] , 1, 2.3 and 4, X is a hydrogen atom and/or Fi atomic number 21-29.3 1.32.37-39.42-44.49 or 57-83 metal ion equivalents i, R1 and R2 are different and each represents a hydrogen atom or, in some cases, one or more hydrogen atoms. hiao imino, phenyleneoxy, phenylene imino, amide, hydro Contains ranod-, ester groups, oxygen-1-sulfur- and/or yanoatoms, and optionally one or more hydroxy, mercagto, imino, epoxy, oxy straight-chain, branched, saturated or unsubstituted by -, thioquine- and/or General formula I or ■, :mu at the saturated terminal position a second molecule, a functional group, or a biological or macromolecule bonded via this functional group. represents a C0-C20-alkylene group, where n and m together can be more than 4. and if X is equal to i1 per metal ion, at least two of the substituents with the condition that it represents this thing].

Compounds of the general formula I in which X represents hydrogen are designated as complexing agents and have a small number of substituents X. Compounds of the general formula I in which at least two of the atoms represent metal ion equivalents are designated as metal complexes. It will be done.

Elements with the above-mentioned atomic numbers forming the central ions of physiologically tolerable complex salts are included in the present invention. Depending on the desired use of the diagnostic agent, it may of course be radioactive.

If the medicament according to the invention is intended for use in clinical diagnosis, complex salts may be used. The heart ion must be paramagnetic, especially for atomic numbers 21-29.42 ．． They are divalent and trivalent ions of 44 and 58 to 700 elements. A suitable ion is For example, chromium (1)-, manganese (II)-, iron (1)-, cobalt (II) -, nickel, I%/(1) -, copper (1) -, graseodymium (I) -, neodymium Muci)-, samarium(1)- and iterbium(1)-ions. So Due to the extremely strong magnetic moment of Gadolinium(1)-, Terbium(1) )-, dysprosium (1)-, holmium (I)-, erbium (1)- Particular preference is given to iron(1) and iron(1) ions. Use of the drug according to the present invention in nuclear medicine diagnosis In order for the central ion to be radioactive, for example the elements copper, co, J′ruto, gallium, germanium, yttrium, strontium, technetium um, indium, ytterbium, gadolinium, samarium and iridium radioactive isotopes are suitable. The use of the agent according to the invention in nuclear medicine includes: The central ion must be radioactive, e.g. elements copper, cobalt, gallium. , germanium, yttrium, strontium, technetium, indium, Radioactive isotopes of ytterbium, gadolinium, samarium and iridium It's appropriate.

If the agent according to the invention is intended for use in X-ray diagnostics, To achieve sufficient absorption of the lent r7 line, the central ion has a higher atomic number. For this purpose must be derived from elements with atomic numbers 21 to 29.42 , 44. Contains physiologically tolerable complex salts with central ions of elements 57-83 It has been found that diagnostic agents are suitable: for example, lanthanum(1)-ion and the aforementioned lanthanide series ions.

The alkylene group contained in R1 or R2 is linear, branched, cyclic, aliphatic, Straight chain, aromatic or arylaliphatic and may have up to 20 carbon atoms Preference is given to mono- to hexamethylene groups as well as C1-C4-alkylenephenyl groups. Roru. If the alkylene group contains one phenoxy group, this is methylene bonded via a group, preferably in the p-position, to the -CH- group of the basic skeleton of the compound of the general formula l There is.

Advantageous functional groups present in the terminal positions of the R1- or R2-alkylene groups are, for example Benzyl ester, ethyl ester, t-butyl ester, amino-1C 1-C6-fulkylamino-, aminocal, hydramenoh, hydrazinoca Le? Nyl-, maleimide-, methacrylamide-, methacryloyl hydrazinoca Is it nil, maleimide amidocal? Nil-, Halogeno-, Mercagtoh, Hydo Radinotrimethylene hydrazinocarbonyl-, aminodimethyleneamide carbonyl Ru-, Promucal〆Ru-, Phenylenediazonium-, Inthiocyanate- , semicarbazide, and thiosemicarbazide groups.

For clarity, some selected R1- or R2-@ conversion funds are listed: -CH, -C6H4-0(CB,)5Co□cu2c4u5゜-CH2-C,1 114-0-CH2-C02CH2C6H5゜-C)12-C6H4-0(CH 2), CONHNH2゜-CH2-C,H,-0(CH2),-8H,-CH2 -C6H4-0 (CH2), ■Kari2゜-CH2-C, H4-0 (CH2), Br 　　.

-CH2-C6H4--CH2-C6H4-0(CH2)5CONHNH-(C .

-CH2-NHNH2, -0M2-8R, -CH2CONH1’v”H□, - (0M2), 5R-CH2-C6H4-0-CH2COBr, -C6H4N HCOCH2Br.

-C6H4-N2. -C6)f, NHC8.

-CH2-CH2-C6H4-0-CB7-CHOH-CH2-NH(C, -C -NHNH,.

-CH2-0-(CH2), -N)(NH2, -0M2-0-C)f2-C-N H=NH,.

-0M2-0-CH2-CH2-)JH2゜-iC-C3C-R-C=C-CH =CRR’.

-(0M2), NH2, -C4H, SCN.

-0802C6H4CH, -8o2C1.

[In the formula, R and R' are the same or different, and each is a hydrogen atom, saturated or unsaturated. C, -C2゜-alkyl group optionally substituted with 91 phenyl groups or phenyl group].

When not all azide hydrogen atoms are replaced by the central ion is one, several or all residual hydrogen atoms are inorganic and/or organic bases or amino acids. Suitable inorganic cations may be replaced by cations such as lithium ions, potassium ions, calcium ions and especially sodium ions.

Suitable organic base cations are in particular those of p-1S- or t-amines, such as ethylamines. Tanolamine, jetanolamine, morpholine, glucamine, N,N-dime Chylglucamine and especially N-methylglucamine.

Suitable amino acid cations are, for example, those of lysine, arginine and ornithine. Roru.

The preparation of the complexing agent according to the invention can be carried out using the general formula Il: where n and m are as defined above and sb , R1' and R2' are different, each containing 91 or several hydrogen atoms or a mixture. imino, phenyleneoxy, phenyleneimino, amide, hydrazide -, ester group, contains one oxygen, one sulfur and/or one nitrogen atom, in some cases 91 one or several hydroxy-, mercagt-, imino-, epoxy-, oxo-, Straight @ monobranched, saturated or unsaturated, substituted by thioxo- and/or amino groups General formula 1' or al' at the terminal position of the sum: Mu　　　　　　1 R# represents a C8-C20-fulkylene group having a second molecule or a functional group. 'iC, -C6-alkyl group] is carried out by saponification of the compound. saponification is prepared by methods known to those skilled in the art. It is carried out depending on fluoroacetic acid.

The production of educts is carried out by the general formula l: [In the formula, n and m are numbers 0.1.2.3 and 4, respectively, and R1# & R29 are Each represents a water X atom or a substituent that can be converted into R1' or i', but n and m together are no more than 4], and the substituents R19 and R2# are different, One represents a hydrogen atom and the other a substituent that can be converted to 81' or 82' ] with the condition that it represents a -substituted polyamine of the general formula H2COOR' (II/), [wherein H1t is chlorine, bromine or is alkylated with iodine and an ester of R3 is listed in 12). This is done in a number of ways.

The reaction is carried out in a polar neutral solvent such as dimethylformamide, dimethyl sulfoxide or In hexamethylphosphorus triamide, acid acceptors such as t-amines (e.g. Thylamine, trimethylamine%N, N-dimethylaminopyridine, l, S&A Zabicyclo (4,3,0:lnonene-5 [DBN]), 1.5 diazobicyclo [ 5,4,0] undecene-5), alkali metal, alkaline earth metal carbonate or - bicarbonates (e.g. sodium carbonate and bicarbonate, -magnesium, - -10°C to 120°C, especially 0°C. It is carried out at a temperature of 50°C to 50°C.

dimer, that is, C(1''-C20-alcohol) contained in R1 and R2 in the formula A compound of the general formula l in which the dilene group is bonded to the second molecule of the general formula IA or ■8 Synthesis can be carried out by methods known in the literature, such as for example with calyl compounds (e.g. acid chlorides). Dicardanylation using amines; mixed anhydrides, activated esters, aldehydes) The addition of two amines using compounds (e.g. oxolyl chloride, glutardialdehyde) Using a substituted alkylene compound with 82 discrete groups, one ring is removed and a nucleophilic group is added. addition/elimination of two rings with the reaction or, in the case of terminal acetyl, an oxidizing reaction Performed by coupling (Cadiot), Chodkir +riez in Viehe -Ac@tylen@s-.

597-648. ff-Cell Dekk-(Mmreel Dekk@r), Ni New York, 1969).

The chains connecting the centers of both molecules can subsequently be modified by subsequent reactions (e.g. hydrogenation 2 X)).

As substituent R19 or R21, in particular hydroxy- and nitrobenzyl- , hydroxy- and carboxyalkyl- and thioalkyl groups (up to 10 carbon atoms) are suitable. This can be done by literature methods known to those skilled in the art. ) ( (h6z, -pharm, Bull, 33.674 (1985), Compe ndium of Org, 5ynthesis 1-5%, Willie and ・Sons Inc. (Wiley and 5ons Ine,), desired location! ! II to N (for example, amino-, hydrazino-, hydrazinocardinyl, methacryloylhydrazinocardinyl-, maleimidoamidecardinyl-, halo (having a mercaguto group, a halocarbonyl group, a mercaguto group), and in this case, In the case of the trobenzyl group.

First, a catalytic hydrogenation is carried out (eg Lylander (P).

Catalytic Hydrogenation Over... Gratinum Metals (CmtalytieHydrag＊n＊tton　o ver Platinum Metalm), Academic Press (A academic Press) 1967), aminobenzyl derivatives There must be.

Examples for the conversion of hydroxy- or amino groups attached to aromatic or aliphatic groups are: Anhydrous neutral solvents such as tetrahydrone, dimethoxyethane or dimethylsulfate Acid acceptors 1 in sulfoxides such as sodium hydroxide, sodium hydride or alkaline Potassium metal or alkaline earth metal carbonates 1 e.g. sodium carbonate, -magnesium In the presence of aluminum, -potassium, -calcium, the temperature between 0 °C and the boiling point of the respective solvent Temperature, especially between 20°C and 60°C! i! I'll give it to you. General formula■:Z -L -Fu (V).

[In the formula, 2 is a discrete group, such as Ct, Br, I, CH, C6H4SO3° or cr, s05' (-, L is aliphatic, aromatic, having up to 20 m carbon atoms represents a monobranched, linear or cyclic hydrocarbon group, and Fu is Reaction with a substrate [in which the functional group at the desired terminal position is expressed (optionally) in an impregnated form]. (W German Patent Application DE-O3 No. 3417413). general Examples of compounds of formula ■ include: BP(CH2)2NH2,kccH2)pH,BrC%C00CH,,BrCH , Co2’Btw.

Br(CH2)4C02CA, BrC)! 2COBr, BrCH2C0h%, C jC horse C00C,H,.

BrcH2CH=CH2 Cal? For example, conversion of the ser　author), Reagunz for Organic Syntheses (Reage ntm for Organie 5 syntheses) 10, 142) , via mixed anhydrides [Org, Prep, Proc, Int, 7.215 ( 1975)) or via activated esters (Adv, Org, Chem, Pa rt　L　472　) can be implemented.

The amine of general formula m required as a starting material can be prepared by methods known in the literature (e.g. Canadian patent (Cawd.

Patent) No. 1178951, Et+r, I, Mad, Chew .

-Chlm-They, 1985.20, 509 and 1986.21, 33 3) optionally substituted with diethyleneamine a [e.g. with rubamic acid bennorester] to the amide and subsequently to the desired amine (especially Starting from an amino acid that is reduced (with Cidaran or L* lithium aluminum chloride) It is done by

When synthesizing a compound of the general formula IO in which R1 represents a hydrogen atom, Fi, before reduction, To remove this strong amide, use a polar solvent such as tetrahydrofuran or dimethyl sulfonate. oxide or dinot in a stan at a temperature of 50°C to 250°C, especially 70°C to 150°C. temperature (possibly in a pressure vessel), e.g. by reaction with ethyl oxamate. It is necessary to perform FL conversion at the α-amino group, and therefore, 3-azo-2-oxo- A geltaric acid diamide derivative is obtained as an intermediate product.

The complexing ligands (and complexes) thus obtained are bound to biological or macromolecules. Well, about that.

It is known that it is enriched in l# in the organ or organ part to be examined. the Molecules like enzymes, hormones, sugars, dextrans, lectins, porphyri pleomycin, insulin, prostaglandins, steroid hormones , amino sugar, amino I! , -egutide, e.g. [/lilysine, silkworm white matter (e.g. globulins and monoclonal antibodies) or lipids (also in the form of liposomes). be. albumin, e.g. human serum albumin, antibody 5 e.g. A conjugate with a monoclonal antibody, antimyosin, or fur powder specific for the This is noticeable. In place of biomolecules, suitable synthetic polymers, such as ethylene oxide, can be used. Polyamides, polyureas, polyethers and polythioureas may also be combined. stomach. The pharmaceutical agents produced therefrom can be used, for example, in tumor- and infarction-diagnosis and oncology. Unreasonable for use in therapy. Compared to polyclonal antibodies, it is antigen-determining It must be specific to the factor, have a certain binding affinity, and be homogeneous (therefore its purification is It has the advantage of being easily produced in practice) and can be produced in large quantities in cell culture. As a monoclonal antibody (for example, Nature) 25 6 volumes, 495 members, 1975).

Those that are directed primarily at antigens located at the cell membrane are particularly important for conjugation. like that Fi, for example, for tumorigenesis, e.g. gastrointestinal area, chest, liver, II cysts. (Blaae), specific for gonadal and melanoma human tumors (cancer Treatment Redetsu (C-nose BeerTreatm@!1tR*pts,) Volume 68, 317.1984, Bl.

5e134, 150.1984) or embryonic cancer antigen (CIA), human villus Membrane gonadotropin (β-HCG) or other tumor site antigens 1 e.g. glycoproteins monoclonal antibodies or their fragments Fab and F (ab2 is suitable) (New Engl, JoMed, vol. 298, 1384.1973, US National Patent (US-P) No. 4331647).

In particular also anti-myosin, anti-insulin and anti-fibrin. - The antibody is overvalued (US Pat. No. 4,036,945 1).

Neptune complex and liposome for liver examination and gallbladder diagnosis or tumor diagnosis complex or clathrate compound with 2ii (e.g. monolayer or multilayer phos Atidylcholine-cholesterol vesicles (Vesikel) are used as ).

For example, the release of immunoglobulins and fragments thereof is known according to the state of the art. What is the bond of radioactive isotopes?

The labeled antibody-conjugate lacks stability or specificity (e.g. tylenetriamine pendaacetic acid = DTPA (result of the use of anhydride). (e.g. Dimgnostie Imaging) 84s 56; Science (5eie+aee) Volume 220, 613.1983; Cancer Drug-7” Ripary r　Drug Delivery　　Volume 1.

125.1984).

The conjugate base according to the invention, on the contrary, has substituents R 1 or R2 through the functional group present at the terminal position of the C8-02゜-alkylene group. It is done. When producing a conjugate between an acid and a biological or macromolecule, a large number of acid residues are generated. may be combined with it. In this case, each acid residue must have one central ion. stomach.

Coupling to the desired macromolecules is similarly possible, for example by Rey, Room8Mor. pho1゜Embrgol, Phya amount @0, Physiology 1981 ．． Volume 18, 241 and J, Phmrm, Sei, Volume 68, 79 (1979) For example, nucleophilic groups of macromolecules, e.g. amino, phenol, sulfhydryl, aldehyde or imidazole This is carried out by reaction of the group with an activated derivative of the Ω-izing agent. As activated derivatives, For example - anhydrides, acid chlorides, acid hydrazides, mixed anhydrides (eg G.

'f, , Kr@jearek and K, L + Tueker, Bi oehem, Biophys.

Res, Coff1Jl! Iun, l　977.581）, Activation Esthetics Nitren, nitren, or isoteocyanate) are suitable for this purpose. vice versa It is also possible to react activated macromolecules with lead acid. For conjugation with proteins For example, C6H4N2, C6H4N1 (COCH2, C6H4NHC8 or c, a4oca2co+2) structure substituents are also used.

In the case of antibody-conjugates, binding of the antibody to the oxidizing agent (or to the metal complex; - The production of the complex-conjugate may be performed in the following order: Ω-forming agent, complexing agent-conjugate, final product. binding agent, metal-complex, and final product) may be used in the order of binding of the antibody to the antigen. There should be no loss or decrease in affinity and binding specificity. This is a glycoprotein Fe part or F nasal t'iF (a b') 2-fragmen by binding to carbohydrate-components in the body.

or by binding to the sulfur atom of the antibody or antibody-fragment. can.

In the first case, first the oxidation of the tsugi unit for the generation of a coubbable formyl group. material desorption must be carried out. This oxidation is carried out by chemical methods known in the literature as (by law) (e.g. J, Histoehem and Cytoehem, vol. 22) .

1084.1974) Oxidizing agents, such as periodic acid, sodium metaperiodate or 1 to 100 in an aqueous solution using potassium metaperiodate. Especially 1 to 20η/I At the concentration of Lt.

The concentration of the oxidizing agent between 0.001 and 10 mmol, in particular between 1 and 10 mmol, in the range - Targets 4 to 8 were carried out at a temperature of KO to 37°C and a reaction time of 15 minutes to 24 hours. In the enzymatic method, % oxidation is determined by the cumulative fermentation concentration l, for example, by galactose oxidase. O~100 units/m, substrate concentration 1~20 da/d, -1 liter 5~B 1 reaction time 1 ~8 hours and at a temperature of 20-40°C (e.g. J, Btol, C hum, vol. 234, 445.1959).

A complexing agent (or metal complex, see above) is applied to the aldehyde produced by oxidation. functional groups such as hydrazine, hydrazide, 19-amine, hydroxylamine.

1 reaction with phenylhydrazine, semicarbazide and thiosemicarbazide 0-37 ℃ 1 reaction time 1-65 hours, pH-value about 5.5-8, antibody concentration 0.5 ~201j9/- and the molar ratio of the complexing agent to the aldehyde is from 1:1 to 1000:1 Combine and stir. Subsequent stabilization of the conjugate is performed, for example with sodium borohydride or water. This di-reducing agent is carried out by reduction of double bonds with boron cyanosodium. Often used in 10-100 times excess (e.g. J, Biol, Ch@w, Volume 254, 4359, l 979).

A second possibility for the production of antibody-conjugates is the disulfide formation of immunoglobulin molecules. We begin with a careful reduction of the bridge; in this case the H-chain of the antibody-molecule is The rufido bridge is detached and closed, while the antigen-binding region O8-8-bond remains intact. Therefore, a decrease in the binding affinity and specificity of the antibody does not actually occur (biochemistry - (Bioehtm, ) 18%, 2226.1979, Handbook O Experimental Immunology (J’1andbook of Exp @rizaental Immunology), Volume 1, 2nd edition, Black Blaekw@ll 5ei entifice Ps+b11eationsχ London 1973.10 Chapter).

This free sulfhydryl group in H-Chinnai Wax is removed by using a complexing agent or *acid complex. at a temperature of 0 to 37°C, a value of about 4 to 7, and a reaction time of 3 to 72 hours.

Antigen-binding range of antibodies! ! It is reacted under the influence of covalent bonding and excessive Examples of reactive groups include the following: halog/a) v-? Roux, Ha! 2rn acetyl, p-mercuric benzoate group i and (crab AF (Mi The groups used in the eha*l)-addition reaction include maleimide, meta C1 group (e.g., J, Aeo・r.

Ch@m, See, vol. 101, 3097.1979).

Non-covalent types of bonds may be used for force, bling, and in this case, ionic bonding 77/7'' change in Lewals supply and hydrogen bridge-superconjunction, with m + force distribution and strength ( Ren-Sadaana-ichi principle) may be given to Kinuso (e.g. avidin-biotin, anti-KJ IIL), in the macromolecule (Malcroa+ol*kiil), p large L1 In the evening of the sky, a small complex is formed: a (host-dust (h・violet-gEl・ Ruri) is also 9 koru.

The coupling principle is that the antibody-Hytridoma (Hyk+r ld.m) to a complex according to the invention with a second antibody-heituridoma. or chemically link both antibodies through a linker (L1ak*r)t- For example, De Noyana N-Og De Américaine Que (27#-Society 4-(J , Amer, Ch. m*5oc-) Volume 101, 3097 (1979) KMd et al. At 90,000 years ago, it was combined with the same amount of pain, and the same amount of pain was given to the patient. Combine avinone (or piotine) T/cv via a car [D, J, Haatsyich et al., J. Nael, Med, 28°1294 (1987 )) This will lead to the production of bifunctional macromolecules. Antibody substitute using the corresponding F(ab)- or F(a b')2-7 fragment of More than anything. ! 1. For pharmaceutical use, bifunctional macromolecules that are enriched in a It can be used for diagnostic or therapeutic purposes in vivo, where it is coupled at the target site and used there for diagnostic or therapeutic purposes. Uninvented complex compounds capable of exerting therapeutic action (possibly piothi/(or Binone) and inject after 7 days. Furthermore, another method is the Gring method. 'If Prot＊la　Tailoring　Food　M@de　 Uses (AIII e Ch * m * S Oe #Symp, ) (1985), 349, reversible radiolabeling (R*v *rsik+l* Radiolab*1ia/ may be used.

Preferred method for producing antibody-7 fragment O compatibility with antibody-A1F! phase Coupling in Ruru. At this time, the antibody or a corresponding F(ak+)2-7 ragmen temperature with a supply inlet and an outlet; 4! 1 Constant phase to be applied to a visible column (@ Eha Aeon 5!洟体). Due to oxidation of 2#f on part of Fe of antibody The column must be protected with a coating before irradiation; to prevent disulfide bridges from forming. As a protection gas (e.g. at the time of F for b-7 ragment O growth) Because the grain is cultivated under argon, the strength of the rice is the same as that of rice. V: The column is washed with too much buffer, leaving reactive groups on the binding protein at the bottom of the column. Use a bath solution as an eluent (for example, if the Pc portion of a monoclonal antibody is periodate solution or 7 fragments for the generation of dehyde groups. (methodethylamine solution) for HA of the dorin group. Reaction 1" From J solution After completely removing the eluent, stop the threshold when the reaction is complete. , followed by thorough cleaning with @buffer solution, and after a long time the solution is free of force and bling components (flI complexes). hydrazide or dithiopyridyl-derivatives) and again thoroughly. For a long time, TPT No. 7 has stopped. Instead of stopping buying for a long time, the so-called Recirculation-symptoms (r・'7el*-8ehalkmmg) f ff: Use In this case, the eluent that has left the column can be directly re-bonded to the column via a ring connection. ! Sent by At this time, the reaction time is actually very short for a good enough person. Achieve a perfect balance. In step 7, wash with buffer again. illusion of retreat If the curing agent is a lagging component, add another layer to the desired acid salt bath. It is complexed in liquids (eg citrate baths) as well as in the subsequent washing steps. Last connected Combined sound - elutes with one or @ slope. Subsequently, if necessary, desalt the Ru. After 1,110 seconds in the buffer, the column was prematurely ejected due to the long coupling step. -ru.

This one word is extremely small in the legal union]ttL and extremely gluttonous li! Idiomatic usage for children It is widely superior in speed and yield, and also enables continuous production of bonded bodies. This is a prerequisite for the economical production of multiple meals in the evening.

The chemical compound thus generated is then subjected to a high speed-ii mortar-liquid chromatograph. pn is produced by chromatography via an ionic exchanger on a microcomputer.

The compound VFi complexing agent of the general formula 1, in which X represents an elementary atom at 7, is thus obtained. . This can be monolayered and purified, or at least two of the t substituents The general formula representing the genus ion per t can be changed to IO*J4 complex ◇U West German Patent Office Publication (DE-OS) No. 340 for the production of metal complexes according to the invention No. 1052 1) By the method published in JAIAI book, atomic number 21-29.3 1.32% 38% 39.42~44.49, 57~830 elements of gold 14 songs or is a metal salt (e.g., 1 L of nitric acid, 1 L of vinegar, 1 L of carbonate, @ compound or g! acid salt) in water and/or low alcohol (e.g. methanol, ethanol or alcohol) (N) or a solution of an equivalent amount of a complex relative of the general formula l in which X represents a hydrogen atom, or is reacted with the suspension and subsequently the azide in the presence of KFi, Hydrogen atoms are converted into fIL by random and/or organic bases or amino acid cations. It is done by

In this case, neutralization is carried out with an inorganic base, for example sodium, potassium or lithium (e.g. hydroxides, **salts or bicarbonates and/or barbed bases, such as especially p-, s- and T-amine, ethano-yamine, molybdenum, 1%/holin, glycamiy, N-methane tyl- and -N,N-trimethylglucamine, and basic 7-mino-1 e.g. For the production of 2 tons of neutral complex compounds, which are applied to ayginine and ornithine. Meni? 1) Aqueous solution or suspension of acidic salt is so weak that the neutralization point is achieved. IAm may be added to the desired base, and the resulting solution may be diluted with Xl to form a concentrated sardine. Mix a neutral salt with water and a suitable solvent, such as lower alcohols (methanol, ethanol, etc.). alcohol, isopro/4-ol, etc.), lower ketones (acetone, etc.).

Polar ether, A/(tetrahydro7ran, nookinane, 1゜2-dimethoxyethane It is possible to precipitate the precipitate by adding (e.g. Il nabeki crystal 1c is often used, ifr desired:jL group is used in Habu. can already be added to the reaction mixture and further reduce the process steps. It was hoped that it would be advantageous for the cargo.

When the complex compound 'aI of a madness contains an acid group of the recognized 10-sided version, It is often made into mixed salts containing medium cations as counterions. I'll take advantage of it.

For example, n is the percentage of the element that brings about the central ion/l- in a water ε suspension or bath solution. A complex salt is formed by reacting with a chemical compound or a compound necessary for neutralizing an organic base. is isolated and made into fI if desired and then completed.

Full-force neutralization can be carried out by adding the required amount of inorganic base to the rounding. base addition The order of addition may be reversed.

The conjugate consisting of the antibody and the complex is incubated with a weak complexing agent, e.g. Licum, sodium chloride, ethylenenoamine chloride, and citric acid, cause a weak binding. Dialysis is performed to remove the combined metal atoms.

In the case of convenient use of complex compounds containing radioactive isotopes, their manufacture: Lazootre - Thirds 7 O Medical Applications (Radiotrae・a vr f・rM@dical Applications) Volume Z1, CRC - Breath (Pr@as) S2 power! Radon (Beam Ratoa L); Lida It was carried out in the manner described in 4.

The preparation according to the present IAEAK- is similarly manufactured using a known method. The compound (in some cases, under the addition of an O additive, which is commonly used in Sidrenus science) in an aqueous medium. If the suspension or solution is suspended or dissolved in It is carried out by a Suitable additives are, for example, physiologically tolerable buffers (e.g. q-methamine), complexing agent (fL is diethylene triamine pen, diacetic acid) 0 If a small amount of beach or necessary, 1. Electrolytes such as sodium chloride or Fi , if necessary - antioxidants, such as ascorbic acid.

VC1 water or saline for enteral administration or other purposes.

1 of 4 formulations according to the invention in salt solution! ! If a suspension or solution is desired , this is combined with one or more auxiliaries commonly used in galenology (e.g. methylcellulose, lactose, mannitol) and/or surfactants (e.g. lecithin, Tw ain”), MyrJ”)) and/or flavoring agents (e.g. (eg, ethereal oil).

It is also possible in principle to produce the pharmaceutical preparations according to the invention without isolation of the complex salt. It is Noh. In either case, the salts and salt solutions according to the invention actually contain uncomplexed toxic gold. No care is taken to perform chelation to avoid containing genus ions. Must not be.

This can be done, for example, by control titration during the manufacturing process to determine whether dye indicators 5, e.g. It can be guaranteed that the Therefore, the present invention also relates to a method for producing complex compounds and their salts. Ru. The last safety step remains to purify the isolated complex salt.

The preparations according to the invention in particular contain from 1 micromol to 1 mol/L of complex salt and typically 0.0 It is administered in an amount of 0.01-5 mmol/yu. This is determined by intraintestinal and parenteral administration. It is.

The complex compounds according to the invention are used for =1, atomic number 21-29.4 Gun diagnosis with 4 and 57-83; t Atomic number 27.29.31.32.38.39.43.49.62.64. radiodiagnostic and in the form of its complexes with radioactive isotopes of elements with Radioactive therapy.

The formulation according to the invention is suitable for use as a contrast agent for nuclear spin tomography. This means that the signal intensity increases after oral or parenteral administration. The expressive power of the WiiTak, which can be obtained by using the nuclear spin tomography machine Kgi, It is extremely suitable for refolding.

Furthermore, this is necessary in order to load the body with as little amount of foreign material as possible. High efficacy and good tolerability required to maintain non-invasive bone properties shows.

Due to the excellent properties of the present invention, the solution of 7 Ksllk degree! l121t 61 Therefore, it is necessary to keep the volumetric load of circulation within an acceptable range and rarely It is important to maintain uniformity throughout the body, that is, 9B-diagnostic agent is NMR- For spectroscopy purposes, it must also be 100 to 1000 times better soluble in water. In addition, the imm according to the present invention has high stability in vitro and is stable in vivo. Therefore, the non-covalently bonded (in itself S Note O) i The release or exchange of a It is only done from time to time.

The formulation according to the invention is generally 0.001 to 5 mmol for use as a pigeon α-diagnostic agent. /-/Akebono, especially Q, is administered in an amount of 0.005 to 0.5 mmol/litre. Use ps i is.

fjl　ji, -d　7　Ia　Muff　(H,J,Wmi　am　) etc., A ! IIIJII of R**atg*mology Volume 142, Page 619 (1 984).

Particularly low doses (below 1 mg/body weight) of m6-specific ONMR-diagnostic agents may be used, e.g. It can be used to detect tumors and myocardial infarction.

Moreover, the complexes according to the invention can be used as sensitive reagents for in vivo corner spectroscopy. and 77 can be advantageously used as to reagents.

The preparation according to the invention is characterized by its unique radioactive properties and the complex compounds contained therein. Details of their use and administration, which are suitable for use with radiodiagnostic agents based on their good stability. For example, @ ``Radio Trainers for Medi 6 /l/-Aprikeikuyo /zu (Radletrac@as for Medical A) pH*atis mm)-CRC-Press (Pr15m).

It is described in I force/radon (B/cm, R/F, Fl/Flum).

Another method of notation using radioactive isotopes is to use positron-emitting isotopes, e.g. ``St'', ``Sg'', ``F・.

55 (・and 4a, positron emission tomography using i■χW, D,, 72 ni Guess(Pk@lpm), M, E,, #Citron Yukoζ Tushion War Tomodarafui Opllf Rain (Pe5ltr・m Ezmlms iea Tomography of Bralm, apriag*a V*r Lay, Berlin, /'Ideybe New York, 1983).

The compounds according to the invention* can also be used in radioimmunotherapy. this is used It differs from the corresponding diagnostic GFR method only by the amount of radioactive isotope used and by Category 21. child The aim is to detect tumors with high-energy short waves with the smallest possible coverage area. The specificity of the antibody used is crucial for the destruction of I.A. This is because the non-specific localization of the antibody complex will destroy healthy targets. 6ru.

The antibody-metal complex according to the present invention, antibody 4L< and antibody-7 lagmate/t, are integrally formed. 97: It serves to transport the object to the target vessel, where it is then transported. Metal ions selected for their destructive properties are capable of releasing radiation that lethally harms IiA vacuoles. +dt-emitting 0 suitable β-emitting ions are 212B1.2f5B, and 2 14B, Dero Yu, this time it's 21! B1 has an advantage. Appropriate photon- and single-ton emission The ion is Ga and this is IS 7 (, which can be obtained by capturing neutrons from a). Ru.

For in vivo administration of therapeutic agents according to the present invention, suitable excipients such as serum or together with physiological saline solution and *(Dfi white matter, e.g. Can be administered together with. At this time, the dose is the strain of M. It depends on the metal ion and the type of image display method.

@therapeutic agent rt%Fk according to the invention is administered extravascularly, especially intravenously (i, v,).

Details of the use of radioactive dr & therapeutic agents can be found in 1, for example Kobukku (R.

Discussed in W, K*zak) et al., TIBTEC, October 1986, 262. It is.

The preparation according to the invention is particularly suitable as a radiocontrast agent, in which case the iodine The signs of homogeneous reaction in nine anaphylaxis detected by the contrast agent contained in the biochemistry using it - It is emphasized that this is not recognized by system analysis. That's Dituta Y style Due to its advantageous absorption customization in the range of higher pipe pressures for ZoStock® It can be superimposed on The formulations according to the invention are suitable for use as lentodan-a contrast agents, e.g. - Similarly to zoatrizoate (9% in Ll~5 mm#/, especially 0.25~1 mm) It was administered in one piece to #o child on Mo/1//.

For details on the use of contrast agents, see e.g. /;ntrastasltt〃(fs;atg@akoatrastasltt@l〃 ), Teime (G, Thi*m*) *Reigzuich (1970) and Tsuy N (P, Thmya) wear%g, BMch@1・r-ai/7you〃Nogukeni/ ・Eiaf″i1hrang 1m d l*R''-tgeadlagaostik, GeTh1*m*, Sututsu Galt.

Discussed in Niyok (1977).

Novel agents and metal complexes to explore new possibilities in diagnostic and therapeutic agents The synthesis of metal complexes and metal complexes was a comprehensive success. New species especially in medical diagnosis This development desirably reveals the development of a picture-one display method.

Compound 4Ij of general formula I' can also be conveniently used as a halogen for the production of antibodies. Wear. The details of Hageten's application for the production of antibodies are as follows: ) Police Department, Immunology, Immunology and Immunity (Immto* l*gy, Itonnnopathology mad lmm1ialty) .

372, Harp@r and EL・v Pssbl, 3rd edition has been done.

The following examples illustrate the objects of the invention in detail.

Rows for two in-vivo clinics Nuclear spin tomography showed evidence of subcutaneous metastasis of gallbladder and colon cancer. A nude macus (Ba1k+/c, female, 201) with a physiological 7 days 4- (4-hi is in the mouth) -3,6,9-tris-(force) wi? Ki7MechiN) Gadolinicum complex (Example 42) 0.0 mmol/9t-venous Administered intravenously.

Before administering the contrast agent, spin 12-co-7-citric acid in the range recommended by JFF and within the skin range. The images were taken at 30 seconds (T, = 400 ms, T8 = 30 ms). Inspection ft. General E. Electric Electric (Firma G@a*ral Electric) (D The actual situation occurred in the 2 Tesla (T.slm) nuclear spin laboratory.

The figure shows three exposures; one before and two after administration of the contrast agent. Gallbladder, administration 30 After a minute, the surrounding liver will be revealed! This is in contrast to the death penalty. Abscess occurs immediately after administration showed 7 Buna N enhancement in limbic iL4 during 30 min, while no apparent N was observed throughout the upper alium for 30 min. Guna y increase is observed.

Example 1 &) 3,6-diade3,6-bis-(1+-butoxycarbonylmethyl)-4 -(4-hydroxybenzyl)-speric acid-bis-(t,-butyl)-dies Tell 4-Hydroxybenzyl-1,2-ethane-diamine as dihydrochloride 15.3 1 F (0,064 mol and potassium bicarbonate 71.149 (0,71 mol) ) in 380d of dimethylformamide (dried over sodium hydride). , bromoacetic acid-t,-butyl ester in dimethylformamide 80- at 35°C. 50.9 is added dropwise. Stir for an additional 2.5 hours at 35°C, after which time the starting product is It is no longer detected by thin layer chromatography. The precipitated potassium bromide was separated by filtration, Concentrate the filtrate. Add water to the residue and extract several times with ether. After drying and concentration Unreacted 1,-butyl bromine acetate is extracted from the ether extract by passing it through silica gel. Purify the ester. A colorless oil of 24-8.9% (63% of theory) was obtained. Ru.

Analysis Calculated value: c63.64 H8,73y4.49023.12 Measured value: c63.78 H8,691i4.41b) 3.6-dia f-3,6 -bis-(1,-butoxycarbonylmethyl)-4-[4-(3-penzyloxy) cycarvinylaminoproboxy)-pencyltosperinic acid-bis(t,-butylene) thyl)-diester 3,6-siade6,6-bis(t,-butoxycarbonyl Methyl)-4-(4-hydroxybenzyl)-speric acid-bis-(t,-butyl) )-diester (Example 1 &) 1-01! (1-61 mmol) of anhydrous tetrahydro Combined with 53■ of NaH (80% in paraffin) in Nran 10d, to which tetra N-(3-bromopropyl)-benzicarbamate in hydro7.5-511 440 μl of ester is gradually added dropwise. - After stirring overnight, a1 shrinkage and silica glue Paraffin oil is separated through a column.

After evaporation of the solvent, a colorless oil 9201119 (70.2% of theory) is obtained.

Analysis Calculated value: C64,92BB, 29 1i5.16021.61 Measured value: c64.99 H8,20NS, 07li 6,6-diade3,6- Bis-(1-butoxycarbonylmethyl)-4-(4-(3-aminozoloboxy) ]-benzyl]-speric acid-pis-(1,-butyl kudiester 3.6-diade3,6-bis-(butoxycarbonylmethyl)-4-(4-( 3-penzyloxycarbonylaminoproboxy)-benzylcosperic acid- Bisou(t,-buterune-gestell!11b) 0.92g (1,1321 1 mol) Soak in t-methanol 20% and add 10% until it no longer absorbs H2-. Hydrogenate over palladium-activated carbon 500~. The catalyst is then filtered off. residual nothingness Color oil is 680W (74% of theory).

Analysis Calculated value 2 c63.59 H9,04H6,18021,17 Measured value: c63.43 BB, 99 1J6.15d) 3. 6-Diade -3,6-bis-(1,-butoxycarbonylmethyl)-4-(4-(3-male imido)-furboxy)-benzylcosperic acid-his-(1,-butyl)- diester 3,6-siade6°6-bis-(t,-butoxy) in 200 d of anhydrous methylene chloride cyclocarbonylmethyl)-4-(4-(3-7minoproboxy)-benzylcose Peric acid-pis-(t,-butylkudiester (Example IC) 6.5 Ji' ( Maleic anhydride 9201t9 (9,4 mmol) in methylene chloride 50- mmol) solution and stir overnight at room temperature. Its edge 1-hydroxybenzoto Riazole 1.27# (9.4 mmol) and dicyclohexylcarbodiimide Add 2-1311 (i 0.34 m% #). Filter out the urea that precipitates after 2 days. The main components were purified by preparative medium pressure chromatography (methylene chloride/ether). make Yield: 3.89.9 (80% of theoretical value) Analysis calculated value: 063.2 2 BB, 09 N5.52023.15 Measured value: C63, 19H8, 15N5.41@) 3. 6-Ziaday 3,6 -bis-(carboxymethyl)-4-(4-(3-(maleimido)-propoxy )-benzylcosperic acid 3.6-siade6.6-bis(1,-butoxycarbonylmethyl)-4-(4 -(3-(maleimido)-proboxy]-benzyl]-speric acid-pis-(t .

-butyl)-diester (Example 1 d) 2-47i (9-2 mmol) The solution was dissolved in 35'Ilt acetic acid and stirred at room temperature for 36 hours. Half of the trifluoroacetic acid in vacuo and pour the remaining solution into 100 g of anhydrous diethyl ether.

Filter the precipitated product with suction and! ! E. Dry. White crystalline powder1. a511 (85%) is obtained. Melting point〉145゜(decomposition) Analysis Calculated value: c53.82 H5,45N7.84032.86 Measured value: C53,89H5,41N7.85 gadolinium complex 3.6-diade3,6-bis-(carboxymethyl)-4-(4-(3-male) imir)-propoxy)-benzylcosperic acid 7.25 ji (13,5 5m Mok) t-0, In ammonium acetate/water 121] Dissolved in 111, in water 1N gadolinium acetate solution 141 is gradually added. 0.1n ammo after 15 minutes Dispense the thoracic segment to approximately 7.5-8°C with Nia solution, heat to 60°C for 15 minutes, and then centrifuge. Remove. The supernatant is a white crystalline material after freeze-drying 9.35% of the theoretical value occurs.

Analysis Calculated value: C41,79H3,79N6.09025.51 G4 22 ．． 79 Measured value: c41.77 H5,76N6.11 (H22,55 ea (atomic adsorption spectroscopy - AM S): 22.72% of gadolinium complex sodium salt The complex obtained as above (3-63, li': 5.26 mmol) was 10 times Dissolve in 5.26% of water and use a microbiulet to prepare 1N strength soda solution. d Add. After lyophilization there are 3.74.9 white crystals.

analysis: Calculated value: C40,44EI3.67 N5.89 024゜69()+1　2 2.06 1a 3.22 Measured value: c40.32 H3, 60N5.95 0G (121,81N & 3.33 Gadolinicum complex dissolved in N-methyl-D-glucamine salt solution 80 N-methyl-D-glucamine 2 to Nium complex 7.85 & (11,38 mmol) -22. ! Add i' (11.38 mmol) in small portions with stirring. base complete Lyophilize after dissolving. Colorless crystalline compounds io, oy remain.

analysis: Calculated value: C42,07H4,89N6.53 028.92G417.76 Measured value: c42.12 H4,77H6,590 gadolinium complex morpholy salt mol of gadolinium complex 5.13.9 (7.43 mmol) dissolved in water 50- 6.49% of a solution containing 101% by weight of Holin is added and subsequently freeze-dried. colorless Crystals 5.76.9 are obtained.

analysis: Calculated value: C43,34II4.41 N7.22 024.74Ga20.2 6 Measured value: C43, 40H4, 32N 7.41 0G (H20, 22 Similar to the recipe for the production of gadolinium complexes the following is obtained: indium complex Calculated value: c46.31 H4,21N6.75 028.28Y 14.45 Measured value: c46-45 H4, 19N6.78.

Calculated value: C40, 86H3, 71N 5.96 024.95Yb24.53 Measured value: C40, 83H3, 81N5.87 0yb24.41 Calculated value: C42, 21H3-84N6.16 025.778m22.02 Measured value: C42, 17H3, 82N75.05 0 Calculated value: C42, 81H 3,89N6.24 026.14Pr20.92 Measured value: c42.18 H3,79N6.22 0 Calculated value: C48,74H4 ,43N7.11 029.76Co9.96 Measured value: c 48.73 H4,71N 7.33 0CO1CLO indium complex Calculated value: c44.53 H4,05N49.31 027.19 Measured value: C4 4,56H3,98N49.27a) 3,6-diade3,6-bis-(1+- butoxycarbonylmethyl)-4-[4-(3-methacrylamido)-propoxy c)-benzylco-sperinic acid-bis-(1+-butyl]-diester acetic anhydride 3,6-diaf-3,6-bis-(1,-butylene) dissolved in ethyl 175'ILt. Toxycarbonylmethyl)-4-(4-(3-aminopropoxy)-benzylco -Speric acid-bis-(t,-butyl)-diester (Example 1c) 7.33 9 (10-6 mmol) Add 1.221 (11.7 mmol) of triethylamine. To this, 1.2 g of methacryloyl chloride ( A solution of 11 mmol) is added dropwise. Stir overnight at room temperature and then precipitate triethyl Filter off the ammonium chloride and concentrate. Column chromatography ($ 6-99 (9-2 mmol; theoretical value) of a colorless oil 87%).

Analysis: Calculated value: C64,23B8.75 N5.61021.39 Measured value: C64,44BB, 52 1J5.63b) 3,6-Siaday6.6- Bis-(carboxymethyl)-4-(4-(3-(methacrylamide)-propo xy)-pencil-tosperinic acid 3,6-diade 3,6-bis-(1,-buto (oxycarbonylmethyl)-4-(4-(3-(methacrylamido)-propoxy) )-Benzylco-sperinic acid-bis(1,-butyl)-diester (Example 2 & ) 2.0.17 (2.7 mmol) in trifluoroacetic acid as described in Example 1e. Transfer to free MI8 forming agent using acid. After drying, colorless powder 1-39 (2-5m molar: 92%).

Melting point: 136℃ (decomposition) Analysis Calculated value: C55,06B6.35 N8.020 3 0.55 Measured value: Css, oi B6.23 N8.13 gadolinium complex A substantially quantitative amount of gadolinium complex is obtained in the same manner as in the formulation of Example 1θ.

Analysis: Calculated value: C42,53B4.46 1J6.19023.6 G(1 23,20 Measured value: C42, 38H4, 30N6.25IM 23.02 oa (AAS): 23.25% The following salt was obtained in the same manner as in Example 10). Sodium salt of nigatrinium complex Calculated value: C41,13B4.31 1J5.99 o22.83oa 22. 44 Ha 3.28 Measured value: C41,20B4.39 N5.89 0Gd21.99 Na 3.27 Gadolinium complex megurumi/salt Calculated values: c43.96 B5.13 N7.32 023.00Ga20. 55 Measured value: c43.89 B5.22 N7.30 0oa21.01 Morpholine salt of gadolinium complex Calculated values: c42.60 B5.53 N6.41 027.45Ga17. 99 Measured value: C42,65B5.60 N6.42 0a) 3. 6-Siade -6,6-bis-(1,-butoxycarbonylmethyl)-4-(4-benzylmethyl) (oxycarbonylmethoxybenzyl)-speric acid-bis-(1,-butyl)-di ester 6.6-siade6.6-bis-(1,-butoxycarbonylmethyl)-4-( 4-Hydroxy-benzyl)-speric acid-bis(1,-butyl)-diester (Example 1!L) 93.06.9 (0.15 mol) was added to 7 g of anhydrous tetrahydro :y (5Q Q　Stir with NaH4,481 (80% in paraffin) in yd. while gradually combining and then adding 150 mCF' of anhydrous tetrahydro7ran at room temperature. Add bromoacetic acid benzyl ester 34.4 & (0.15 mol) t-1a.

- Suction filter the precipitated sodium bromide while stirring overnight, concentrate and diethyl ethyl ether. Excess inorganic components are removed by washing with water. MgSO After drying in step 4, the solvent is removed and purified via a silica del column. colorless oil 75.2.9 (65% of the theoretical value) is obtained.

analysis Calculated value: c65.43 Yo8.10 N3.63 022.82 Measured value: C 65,23B8.17 h3.58b) 6,6-dia f-3,6-bis-(ka (ruboxymethyl)-4-(-4-benzyloxycarbonylmethoxybenzyl) -speric acid 6.6-diaf-3,6-bis-(1,-ptoxycaxfnylmethyl)-4-( 4-benzyloxycarbonylmethoxybenzyl)-speric acid-bis-(1+ -butyl)-diester (Example 3a) 5-499 (8,1 tn mol) Fluoric acid @501j! Heat to 50° C. and leave overnight at room temperature. then anhydrous A clear solution in 500 d of ether is poured in and the precipitate is filtered off with suction. White crystals after drying 2 ．． 4.9 (54.5% of the theoretical value) was obtained, which indicates that gas generation occurs above 150°C. Break it down below.

Analysis Calculated value: C57,1311!5.53 1J5.12032.20 Measured value: C57,21B5.51 Na,98 gadolinium complex as described in Example 1e. Manufactured by the method described above.

analysis Calculated value: C44,56B3.88 N3.99 025.11oa22.43 Measured value: C44,42 3-85 Na, 05G (121,93 G (1 (AAS)) 22.38% Similarly, the following salts can be obtained by the method described in Example 1θ. um salt analysis: Calculated value: C43,20B3.62 N3.87 024.35G (121,7 52JIL 3.1 8 Measured value: 043.14 B5.66 N3.85 0Ga 21.1 5 Na 3.09 Calculated value: C44, 28H4, 84N4.69 028.60G (117,57 Measured value: C44, 50H4, 81N4.75 0G (117, 23 Calculated value: C45,79H4,481!5.34 024.39G419.98 Measured value: C45, 81H4, 41N 5.37 0G (119,59 False 4 &)3,6-diaf-3,6-biy,-(t,-butoxycarbonylmethyl-4 -(4-hydrazinocarbonylmethoxybenzyl)-speric acid-bis-(1, -butyl kudiester Pot 3,6-diade 3,6-picu (t, -butoxycarbonylmethyl]-4-(4-benzyloxycarbonylmethoxy benzyl)-sperine-bis(t,-butyl)-diester (Example 3 a) 6.8 & (8.82 mmol) in 50 WLt of ethanol 1-1id dropwise at 5-10°C and stirred overnight at room temperature. after that Cut it in half! ! Pour into B2O 400" and extract several times with ether. Dry and After removing the organic phase, it is purified through a silica gel column. Colorless oil5. 85:9 (95.4% of the theoretical value) is obtained.

analysis Calculated value: c60.49 BB, 4j 1i8-06 023. [)2 measurement value :C60,60B8.31 N8.07b) 3.6-Siaday6.6-bis- (carzoxymethyl)-4-(4-hydrazinocarbonylmethoxybenzyl)- Speric acid 3.6-diade3,6-bis-(1+-butoxycarbonylmethyl)-4-( 4-Hydrazinocarbonylmethoxybenzyl)-speric acid-bis-(t,-butyl) (Example 4a) 7-7Ji' (10-9 mmol) was dissolved in trifluoro Leave to stand at room temperature for 2 hours in acetic acid 80°C.

Then pour into anhydrous ether and decant. 10% ether for another hour after 7 Stir with triethylamine solution 100'ILt, filter with suction and dry in vacuo. 2 white crystals with melting point 185°C (decomposition) 4.5.90yield 4.5g (89% of theory) ).

analysis Calculated value: C48, 50115, 57m11.90 o34.0 Measured value: c48 ．． 27 Manufactured using N5.56 and N11.93.

analysis Calculated value: c 36.53 B 3.71 N 8-96 025.61G (125, 17 Measured value: C36,60N3.68 N8.89G (124,51 Gd (Mumu S): 25.26% The following salt is obtained in the same manner as the recipe of Example 1θ : is the sodium salt of trinium complex analysis: Calculated value: C35,29B3.42 N8.66 024.74G (124,3 1Na 3.55 Measured values: C35, Ro3 N3.40 N8.71.

Gd 24.01 Na 3.59 Calculated value: C38,08B4.91 N 8.54 029.27 () (L 19.17 Measured value: C3EL12 H4, 90N8.49 0G419.20 Morpholine salt of gadolinium complex analysis: Calculated values: C38,86B4.59 N9.85 024.76Gd22. 12 Measured value:・03B, 82 H4, 48N9.89 0Gd22.1 6 Example 5 a) 3. 6-diade 3,6-bis-(1,-butoxycarbonylmethyl )-4-(4-benzyloxycarzanylpentamethyleneoxybenzyl)-su Peric acid-bis-(t+-7” thyl)-diester According to the formulation of Example 3a, 3, 6-diade3,6-bis-(t,-butoxycarbonylmethyl)-4-(4- Hydroxybenzyl)-speric acid-bis-(t,-butyl)-diester (e.g. 1a) 5.5 Ji’ (5.6 mmol) and 6-bromocaproic acid base from 1.6.9 (5-6 mmol) of esters to 3.69 (theoretical) colorless oil. 78%) t-obtained.

analysis Calculated value: C66,80H8,531J3.38 o21.27 Measured value: C'6 6-72 HB-49N3-40b) L 6-dia f-3,6-bis-(ka (ruboxymethyl)-4-(4-benzyloxycarzanylpentamethyleneoxy) 3,6-siade6,6-bibenzyl)-speric acid according to the formulation described in Example 3b. Su-(t,-butoxycarbonylmethyl)-4-(4-benzyloxycarbonylmethyl) Lupentamethyleneoxybenzylene-suberic acid-bis-(t,-butyl)-di Esther (Example 5’) 12-31! White crystals from (14.8 mmol) 8. 25 g (92% of theory) is obtained.

Melting point = 188℃ (decomposition) Calculated value: C59,79N6.35 N4.64 029.20 Measured value: C5 5,92]]1i6-41 N4.74 Gadolinium-complex By the method described in Example 1θ, a gadolinium complex can be obtained with almost quantitative yield.

analysis Calculated values: c47.60 N4.66 N3.70 023.25G620. 77 Measured value: C47,38H4,67N3.52G (120,65 Analogous to the formulation of Example 1e, the following salt is obtained: Calculated value: C46-26 H4,40 13-59022-29Gd 20.19 M& 2.95 Measured value: C46, 25H4, 56N3.60 0oa 20.09 Na 2 ．． 99 Meglumine salt of gadolinium complex Calculated value: C47,47B5.59 1J4.48 025.63ea16.79 Measured value: C47,39N5.57 N4-49 0G (11 (5,63 Calculated value: C48,44N5.14 N4.98 022.770d18.65 Measured value: C48, 38B5.17 N4.930Ga I EL37 Example 6 a) 3,6-diade 3,6-bis-(1,-butoxycarbonylmethyl)-4 -(4-hydrazinocarbonylpentamethyleneoxybenzyl)-speric acid- Bis-(1,-butyl)-diester 3,6-diade -3,6-bis-(t,-butoxycarbonylmethyl)-4-(4-benzylmethyl) (xycarbonylpentamethyleneoxybenzyl)-speric acid-bis-(t, - Butyl)-diester (%j5a) 6-35# (7,68 m-r-le) Colorless oil 5. [ ] N7.9 (88% of the theoretical value) is obtained.

analysis Calculated value: C62,37N8.85 N7.46 021.30 Scooping value: C6 2,28N8.84 N7.51b) 3.6-diade3,6-bis-(cal) boxymethyl)-4-(4-hydrazinocarbonylpentamethyleneoxybendi )-speric acid 3,6-siade6,6-bis-(1,-butoxyca Rubonylmethyl-4-(4-hydrazinocarbonylpentamethylene-oxyben Zyl)-speric acid-bis-(t,-butyl)-diester (Example 6 a) 2 -66ji (3.54 mmol) to white crystals 1.699 (91% of theoretical value) ) is obtained.

Melting point: 210℃ (decomposition) analysis Calculated value: C52,46N6.50 N10.64 030-38 Measured value: C 52,51N6.39 N10.70 By the method described in Example 1e, the quantitative determination of Obtain gadolinium-complex with station name.

analysis Calculated value: C40,57N4.59 N8.22 023.500a23.09 Measured value: C40, 60N4.52 N8.21oa23.0 Similar to the recipe in Example 1e, the following salts are obtained: Sodium salt of Gatrinium complex Calculated value: C39, 31H4, 50N7.97 022.76Gd22.37 Na 3.27 Measured value: c39.26 N4.31 N7.90 0G (121,97Na 3.27 Meglumine salt of gallium complex Calculated value: C, 11, 13B5.52 N7.99 027.39G (117, 95 Measured value: C41, 20115, 55N7.87 0G (117,81 Calculated value: C42,28N5.12 N9.13 022.94G (120,5 0 Measured value: C42, 31B5.07 N9.14 0G42Q, 1i Example 7 a) 3. 6-Diaza-3,6-bis-(1+-butoxycarbonylmethyl -4-[4-(methacryloyl]-hydrazinocarbonylpentamethyleneoxy) benzyl)-speric acid-bis-(t,-butyl)-diester 3.6-siade6.6-bis-(1,-butoxycarbonylmethyl)-4-( 4-hydrazinocarbonylpentamethyleneoxybenzyl)-speric acid-bis -(t,-butyl)-diester (Example 6a) 4.17 & (!5.56 mmol) t -Dissolved in 50ml of anhydrous dichloromethane and added 0.6mt of triethylamine. Ru. Then 0.6 I of methacryloyl chloride in 10 g of dichloromethane was added at 0°C. Add solution dropwise and stir overnight at room temperature to precipitate triethylammonium chloride. filter. After filtration through silica sol with acetic acid ester, removal of the solvent A colorless oil of 3.14.9% (69% of theory) is obtained.

analysis Calculate! :C63,05H8,61N (5,84021,48 Measured value: C62,9 8H8,70B6-s2b) 3,6-diazu-3,6-bis-(carboxymethy )-4-(4-(methacryloyl)-hydrazinocarzanylpentamethyleneol) xybenzyl)-speric acid By the formulation described in Example 3b, 3,6-siade 3°6-bis-(t,-butoxy) carbonylmethyl)-4-(4-(methacryloyl)-hydrazinocarbonylpe ntamethyleneoxybenzyl)-speric acid-bis-(1,-butyl]-dies Tell (Example 7 a) 3. White crystals 1.921 from [j & (3,66 mmol] ! (88% of the theoretical value) is obtained.

Melting point = 165°G (decomposition) Calculated value: C54, 53H6-44N9.42 029.59 Measured value: C54, 6D　H6,31N9.51 Gad with almost quantitative ink collection by the method described in Example 1e. A linium complex is obtained.

Calculated value: C43,30B4.71 N7.48 023.50ea20.99 Measured value: C45, 24B4.69 N7.43ea21.20 Analogously to formulation 1e the following salts are obtained: Calculated value: C42,01H4,57B17.25 022.80OL 20.37 　Na　2.97 Measured value: cal, 96 H4,55N7.30 0G (120,03Na 3.01 Calculated value: c43.21 I! 5.65 N7.41 027.080d16 ．． 63 Measured value: C10,20B5.70 N7.38 0oa16.53 Calculated value: C44,54B5.30 N8.37 022.96Gd, 18.8 1 Measured value: C44,4511!5.38 N8.34 00418.80 Example 8 &) 5. 6-Diaza-3,6-bis-(1,-butoxycarbonylmethyl )-4-(4-carboxymethoxybenzyl)-speric acid-pis-(t,-but chill)-diester 3.6-diade3,6-bis-(1,-butoxycarbonylmethyl)-4-( 4-benzyloxycarbonylmethoxybenzyl)-speric acid-bis-(1, -butyl)-diester (Example 3 a) 9.59 (0,012 mol) in anhydrous form Dissolve in 100 d of tetrahydrofuran and do not absorb hydrogen (until 10% P d, /c 2 hydrogenated in the presence of g. After suction aeration, the solvent is removed in a rotary evaporator, The material is further dried under o.o.l. The resulting mucilaginous oil was 8.3 3# (99% of the theoretical value).

analysis Calculated value: C61,74H8,29N4.11 025.84 Measured value: C61, 82B8.17 N4.12b) 3.6-diazu-6,6-bis(1,-buto (oxycarbonylmethyl)-4-[4-((2,3,4,5゜6-pentahydroxy Cyhexyl)-methylamino)-carbonylmethoxybenzylco-speric acid- Bis-(1,-butyl)-diester 3.6-siade6.6-bis-(1,-butoxycarbonylmethyl)-4-( 4-Carboxymethoxybenzylcousperate-bis-(t,-7”thyl)- Dissolve 1.36 g of diester in 50 g of tetrahydroalane and add triethylamine. Add O-39 (3 mmol). Carefully store Tetrahyroir 201L at -5°C. Add 0-297i (2-02 mmol) of chloroformic acid inbutyl ester in t Finally, aqueous solution 5 of N-methyl-D-glucamine 43C1# (2.2 mmol) Add Rt. After stirring for 30 minutes at 0°C, remove the cold bath and heat to room temperature. of solvent After removal, the residue is purified by chromatography on silica gel. Above 52℃ 1.438 (83% of theory) of a white crystalline substance that decomposes under a brown coloration. obtain.

analysis: Calculated value: C58,78H8,34N4.89 027.96 Measured value: C58,6 2H8,32N4.79C)3,6-diade3,6-bis(carboxymethyl ) to 4-(4-((2,3,4,5,6-bentahyP C2xyhexyl)-mer Tylaminol/L-bonylmethoxybe/zyl]-speric acid 6,6-diaz-6,6-bis-(t,-7” toxic) as described in Example 1e. (bonylmethyl)-4-(4-((2,3,4,5,6-pentahydroxyhexy )-methylamino)-carbonylmethoxybenzylcosperinic acid-bis-( t,-butyl)-diester 0.789 (0-91 mmol) melting point 132° 432 Mg (75% of theory) of the title compound C (decomposition) are obtained.

Analysis 2 Calculated value: c49.28 B6.20 x6.63 037-87 Measured value: C 49,19B+5.21 N6.46 Gadolinium monocomplex Similar to the recipe 1e, the Gad+7　nium complex is obtained in almost quantitative quantities: analysis: Calculated value: C39,63H4,6N5.33 030.460d19.95 Measured value: c39.72 B4.66 N5.32G (119,75 Ga (AAS) 20. [ ] B111L amount % Similarly to the prescription of 1e, the following Obtain: Calculated value: c38.56 B4.35 Ns, is 029 ．． 63ea 19.41 1Ja 2.83 Measured value: C38,50B4.54 N5.09Gd 19.50 lJ& 2.81 total X value: C40, 31B5.43 N5.69 032.55G (1 15,99 Measured value: C40, 29B5.40 N5.67ea15.80 analysis: Calculated value: c41.23 115.07 N6.41 029.29G+11 7.99 Measured value: C41,20B4.98 N6.37Ga17.69 Hook 9 a) 0-benzyl-N-)! 7 fluoroacetyl terosine 0-benzyl tyrosine 1 12.5 Ji' (0.41 ml) was suspended in anhydrous methanol 11 and heated to room temperature. Then 58.9 m (0.42 mol) of triethylamine are added. trifluoro vinegar After addition of acid ethyl ester 6731/(0,53 mol), moisture was removed for 130 hours at room temperature. Stir under exclusion. Separate unreacted starting materials and remove volatile components from acetate/water. Remove by shaking with hydrochloric acid. The acetate ester phase is decolorized with activated carbon. of solvent After evaporation, 120.71 colorless crystals (80% of theory) are obtained.

analysis Calculated value: C58, 85B4.39 N3.81 017.42F 15.5 1 Measured value: C58, 78H4, 29N3.79? 15.57 b) 0-Benzyl-N-trifluoroacetyltyrosine-(2-carbobenzoxyrosine) Cyaminoethylene) -7 Mid 0-Benzyl-N-trifluoroacetyltyrosine (Example 9a) 1 B-5IC 50.4 mmol) was dissolved in 200 d of anhydrous tetrahydrofuran, and Et3N 7 m and then 4.8117 (50-8 mmol) of chloroformic acid ethyl ester is added, keeping the temperature below -10°C. After addition is complete, at this temperature for 30 minutes. Stir, add the same amount of pre-cooled triethylamine, and dimethylformamide. 1-”N-(2-aminoethylcoucarbamic acid benzyl ester in 100N - Drop a water-cooled solution of salt iai 1.6 & (50.4 m% l). -10℃ Stir for another 30 minutes, then bring to room temperature while stirring, then heat to 30°C for 10 minutes. do. The solvent is then removed in a rotary evaporator and poured into 75011 Lt of ice water. sucking crystals Filter, wash with ice water, and dry. Yield is 26.9! i’ (theoretical value 9 4%).

Melting point = 189-190°C.

analysis Calculated value: C61,87B5.19 N7.73 014.71P 10.48 Measured value: C61,90B5.08 N7.77? 10.43 C) 0-benzyltyrosine-(2-carbobenzoxyaminoethylene)-amino P O-benzyl-N-trifluoroacetyltyrosine-(2-carbobenzoxy aminoethylene)-amide (Example 9 b) 25.9, li+ (47,8m mol) of KtO was suspended in 111,300 g of KtO and 7.29 (1 mol) of sodium borohydride was suspended in 111,300 mol of KtO. 91 mmol) was added in small amounts. After stirring overnight at room temperature, acetone 50′ILtf : Add, remove the solvent, add 5001L of H2O, and extract several times with acetate. Ru. After drying and concentration, the organic phase forms white crystals with a melting point of 145° C. ia, a! I (theoretical value 88%).

analysis Calculated value: C69,77H6,53N9.38 014.29 Measured value: c69.7 9 B6.55 N9.35a) Tyrosine-(2-amine ethylene)- Amido O-benzyltyrosine-(2-carbobenzoxyaminoethylene)-a Mido (Example 9 Q) 42.3 g (94-6 mmol) t-methanol 1.11 Add 10% palladium-activated carbon 2I, and the hydrogen receiver is no longer charged. Hydrogenate without stirring until the mixture is completely dissolved. The catalyst is filtered off and the solvent is evaporated.

17 g of colorless crystals (theoretical value of 86 %) occurs.

Melting point: 138-141℃ analysis Calculated value: C59,17B7.67 N18.81 014.33 Measured value: C’59.23 B7.51 118.90 li 3-7 day 1-(4-hydro xybenzyl)-pentane-1,5-diamine-trisalt dispersion Tyrosine-(2-7minoethylene)-amide (Example 96) 6.55 ji ( 29.3 mmol) was suspended in anhydrous tetrahydrofuccine 16ON, Tylene glycol dimethyl ether 751 and boron trisulfide-etherate - from NaBH35,8fi in complex 54] with a gentle upflow of anhydrous nitrogen and always The solution was passed through with stirring. Stir overnight at 60°C, then methanol at 20°C. 60 g of water was added dropwise, and hydrogen chloride was introduced while cooling with water. Then boil for a short time and filter with suction. pass The tribasic acid salt is obtained in the form of colorless crystals.

Melting point: 250℃ (decomposition) analysis Calculated value: C41,45H6,95N13.18 05.02C133,37 Measured value: C41,37Ei6.89 1113.14C133,51 f) 3t 6t 9-trifur r-4-(4-hydroxybenzyl)-3 ,6,9-)li(1,-butoxycarbonylmethyl)-undecanedioic acid ~ bis -(1,-butyl kudiester 3-7day 1-(4-hydroxybenzyl)-pentane-1,5-diamine tri Base salt (Example 9 e) 2.07 & (6.5 mmol)' with 5 sodium bicarbonate ．． 29 and bromoacetic acid-1,-butyl ester 6.34 & (82-2m model) 3,6-diadepisu(1,-butoxycarbonylmethyl)- 4-(4-hydroxybenzyl)-speric acid-bis-(t,-butyl)-die Manufactured according to the formulation of Stell (Example ia). Colorless oil 3.549 (68.8% )t-get.

analysis Calculated value: C63,13I! 8.91 B5.38 022.56 Measured value: C6 3,2M B8.9 [I NS-42g) 3.6-) Rear day 3,6,9- ) Lee(1,-butoxycarzanylmethyl)-4-C4-(3-benzyloxy carbonylaminopropoxy)-benzyl)]-]undecanoic acid-bis-t, -butyl)-diester 3. 6. 9-) Liaday 3. 6. 9-) ri- (t,-butoxycarbonylmethyl)-4-(4-hydroxybenzyl)-u Ndecanoic acid-pis(t,-butyl)-diester (Example 9 f) 4.6 ji (5.90 mmol) to a colorless oil 'IEJ4 according to the formulation described in Example 1b. ．． 2.9 (vehicle collection 74%).

analysis Calculated value: C64,30H8,5115-76021,41 Measured value: C64,2 0H8,65B5.82h) 3p 6t 9-Tori 7 v"-3,6,9-)!J-(t,-butoxycarbonylmethyl-4 -(4-(3-aminopropoxy)-benzyl]-wandecanoic acid-bis-(1 +-butyl)-diester 3.6.9-) by the method described in Example 1C! J Azo 3. 6. 9-) Li -(1,-ptoxycarbonylmetfk)-4-C4-(3-benzyloxycal (bonylaminopropoxy)-bis/di-undecanoic acid-bis(1,-butyl) )-diester (Example 9 g) 3.91 (4-8 mmol) are hydrogenated. colorless A viscous oil is obtained. Yield: 3.17 g (97.3% of theory).

analysis Calculated value: C62,13B9.15 B6.69 021.02 Measured value: C62 , 97 only 9.01 B6.62i) 3t 6, 5) - Dori Ata'-3,6,9-) Li-(1゜-butoxycarbonylmethyl)4 -C4-C3-Cmaleimido)-propoxy)-benzyl]-undecandioic acid- bis(t,-butyl)-diester maleimide by the method described in Example 1d. 3,6,9-tri7day 3,6,9-)(1,-butoxy) with 91% yield. cyclocarbonylmethyl-4-(4-(3-aminopropoxy-benzyl)-unde obtained starting from Kanni m-bis-(t,-butyl)-diester (Example 9h) ( colorless, viscous oil).

analysis Calculated value: c62.86 B8.35 B6.1o o22.62 Measured only: c62.71 B8.33 B6.10-+) 3F 6t 9-3,6,9-) li-(carboxymethyl) -4(4-(3-(maleimido)propoxy)-benzyl]-undecanedioic acid example The free pentaic acid was converted to 3.6.9-triade 3, at 89% as described in 1e. 6,9-tri(t,-butoxycarbonylmethyl)-4-[4-(3-(male) imido)-propoxy]-benzyl]-cundecanedioic acid-bis-(t,-butyl )-diester 1191) is obtained as a white powder. Melting point:〉1 61℃ (decomposition) analysis Calculated value: C52,82B5.69 N8.80 032.67 Measured value: c52 ．． 72 B5.63 N8.86 gallium complex Analysis of the formulation of Example 1e yields a quantitative determination of the gadolinium complex t-a.

analysis Calculated value: C42,52H4,20N7.08 02 (5,30Ga19.88 Measured value: c42.58 B4.29 1J7-83 0Gd19.89 oa (AAS): 19.73% Obtain the following salt as described in 1e: Calculated value: C40, 28B3-74 B6.71 024.91 () (i 18 ．． 83 M & 5.50 measurement value: c40.23 B3-77 B6-90 0Gd i 8.58 N & 5.47 Calculated value: C42,7D B5.85 N7.28 030.52ea13.63 Measured value: C42-58B5.69 1J7.35Gd13.51 Calculated value: C44,89B5.12 N8.72 024.91oa16.32 Measured value: C44,93B5.15 N8.77G (116,15 Similar to the recipe for manufacturing gadolinium complex, calculate the following: c44.93　H 4,44) B7-49 027.79 engineering n15.34 Measured value: C44,94B4.61 N7.44 work n15.32 Ittelikmu complex Calculated value: C46,48B4.59 N7.75 028.75Y 12.43 Measured value: C46,50B4.62 N7.61Y 1 2.45 Calculated value: cal, 68 E, a, 12 N6.95 02.5.79yb2 1.45 Measured value: C41,55Ii4.17 N6.81 Calculated value: C42,89H4 , 24N7.15 o26.538m 1 9.1 8 Measurement 41: c 42.81 H4, 23N 7.20Sl 1 9.3 1 Calculated value: c43.42 H4,29N7.24 026.86Pr 1 a, i 9 Measured value: c 43.32 H4,43y 7.31pr18.20 cobalt complex Total X value: c48.56 B4.80 N8.09 030.04 CO8,5 1 Measured value: C48,58H4,73N8.18CO8,36 10 3, 6. 9-) Riaday 4-(4-benzyloxycarbonylmethoxyben) Zyl)-3,6,9-tri(1+-butoxycarbonylmethyl)-undecane Nishun-bis(1+-butyl)-diester 3.6.9-)ria+1j-4-( 4-Hydroxybenzyl)-3,6,9-)-(1,-butoxycarbonyl) Bis(t,-butyl)-undecanedioic acid and benzyl ester in bromine vinegar From 0.549 (2.54 mmol) of the colorless white powder obtained by the formulation described in Example 3a, 1.35. li' (1.45 mmol) was obtained (62% of the theoretical value).

analysis Calculated value: C64,70B8.36 N4.52 022.4 Measured value: c6 4.91 H8, 31N 4.55b) 3+ 6p 9-Triade 3, 6.9-)Lee(carboxymethyl)-4-(4-benzyloxy-carbonyl methoxybenzyl)-undecanedioic acid 3, 6. 9-) Rear day 4-(4-be) benzyloxyfJkM nylmethoxy-benzyl-3,6,9-)! J-(1,- butoxycarbonylmethyl]-cundecanoic acid-bis-(1+-butyl)-die Stel (Example 10a) from 5.3.9 (5.71 mmol) to the formulation described in Example 3b. A whiter solid 3.0 & (82% of theory) is obtained. Melting point = 145℃ (min. solution) analysis Calculated value: c55.63 B15.75 N6.48 032.11 Measured value: C55:69 B 5.70 N 6.43 Gadolinium epilepsy in Example 1θ Manufactured by the method described.

analysis Calculated value: C44, 93H4, 27N5.24 025.93G+119.61 Measured value: C44,87B4.14 N5.30G (119,41 ea (AAS): 19.62% The following salt was obtained similarly to the formulation described in Example 1e. Sodium salt of Niga P linium complex Calculated value: c42.60 B3.81 N4.96 o24.59G418 ．． 59 NIL 5.43 Measured value: C42,54B3.87 N4.99G418.38 1Ja 5. 47 Meglumine salt of gadolinium lead body Calculated value: C44, 32B5.74 N5.87 030.86'0413.1 8 Measured value: C44,50yo5.65 1J5.88G (113,07 Morpholine salt of gadolinium complex Calculated value: c46-85 B5.17 N7.18 024.63G (116 ,14 Measured value: c46.57 B5.15 N7.25G, ll 1 5.97 Example 11 ! L) 3,6.9-)riaday-4-(4-hydrazinocarbonyl-methoxyben) Jill)-3,6,9-)! 7-(1,-Butoxycarbonylmethyl)-kundeca nionic acid-bis(t,-butyl)-diester 3.6.9-) reared 4-(4 -benzyloxycarbonylmethoxybenzyl)-3,6,9-)! J - (1 ,-butoxycarbonylmethyl)-undecanoic acid-bis(1,-butyl)- Diester (Example 10a) 12-6. ! ii' (13,57 mmol) to Example 4a A highly viscous colorless oil at room temperature 9.69 (83% of theory) get.

analysis Calculated value: c60.61 B8.63 N8.21 o22.53 Measured value: C60,47H8,70N8.12b) 3,6t 9-Triade 3,6,9 -tri(carboxymethyl)-4-(4-hydrazinocarbonylmethoxyben) 3.6.9-Triade 4-(4-hydrazinocarbonylate)-undecanedioic acid (methoxybenzyl)-3,6,9-)ly(1°-butoxycarbonylmethyl) ) undecanoic acid bis-[t,-butyl kudiester (a) 6.89 (7-9 mmol) is reacted with trifluoroacetic acid according to the recipe described in Example 4b. . White crystals after post-treatment 3.11! (67% of the theoretical value) is obtained. Melting point: 180℃ (min. solution) analysis Calculated value: c48.33 B5.81 12.25 033.59 Measured value: C4 8,46B5.79 N12.3 [3 gadolinium complex in the formulation described in Example 8 Manufactured from

analysis Calculated value: 033.06 H4,16B9.64 026.45G421.66 Measured value: c32.98 B4.08 B9.55G421.03 G(L(AAS)21.57% The following salt is obtained by the recipe described in Example 18: Calculated value: c35.88 HS, 66 B9.09 o24.94Gd 20.42 Na 5.97 Measured value: C35,78B3.57 B9.00G420.25 Na 5. 96 Calculated value: C39,85B5-69 N8.79 031.560 (L 14. 10 Measured value: C39, 8115, 70N8.73G (114,00 Morpholine salt of gadolinium complex Calculated value: c41.46 B5.16 n10.91 024.94Ga17 ．． 51 Measured value: C41,41B5.17 1JI O,99G (117,48 Example 12 a) 3. 6. 9-) Ri Other-3, 6, 9- Tori-(1 ゜-Butoxycarbonylmethyl)-4-(4-benzyloxycarbonylpenta methyleneoxybenzyl)-untecanniic acid-bis(t,-butyl)-dies Tell 3,6.9-)'JAzo5.6,9-1 Lee(1, -butoxycarbonylmethyl-4-(4-hydroxybenzyl)-undecane Diacid-bis(1+-butyl)-diester (Example 9f) 7-39 (9,36m mol) and 6-bromocaproic acid benzyl ester 2-671 (9-36m mol) gives 7.19 N (78% of theory) of a colorless oil.

analysis Calculated value: C65,89H8,70N4.26 021.13 Measured value: C65,7 6H8, 62N4.30b) 3. 6. 9 - Tori A f-3 ,6,9-) Li-(carboxymethyl)-4-(4-benzyloxycarboxylic acid) (rubonylpentamethyleneoxybenzyl)-undecanoic acid The formulation described in Example 3b butoxycarzanylmethyl)-4-(4-benzyloxycarbonylpentamethyl) (renoxybenzyl)-undecanoic acid-bis=(1+-butyl kudiester) (Example &) 6-931! (7,04rnmol) to 4-30g of white crystals ( 87% of the theoretical value)'t-obtained.

Melting point: 173°C (decomposition) analysis Calculated value: c58.02 H6,44N5.97 029.55 Measured value: c58 ．． 02 B6.34 N5.96 Gadolinium monocomplex The gadolinium complex is obtained in almost quantitative yield by the method described in Example 1e. analysis Calculated value: C47,59yo 4.93 N4.89 024.24Ga18.32 Measured value: c47.50 B4.83 N4.98G (118,22 Analogous to the formulation described in Example 1e, the following salt is obtained: Calculated: C45,27]II4.4 7 N4.65 023.06 ()d 17.43 1J! L 5.09 measurement Value: C45, 33H4, 45N4.61oa 1 7-51 Ha 5 ．． 11 Meglumine salt of gadolinium complex ttX value: C46, 18B6.13 B5.60 029.470 (112, 59 Measured value: C46,17B6.14 B5.51G (112,61 -morpholine salt of gadolinium complex Calculated value: c48.96 B5.67 N6.79 023.29G+115 ．． 26 Measured value: 048.99 B5.61 N6.78Ga 15.17 Example 13 &) 3. 6. 9-) Refday 3. 6. 9-tree (1゜-bu (toxycarbonylmethyl)-4-(4-human 2dinocarbonylpentamethylene) xybenzyl)-undecanoic acid-bis(t,-butyl)-geste Example 4a 3.6.9-)riaday3.6,9-)ly(1,-butoxy) according to the described formulation. carbonylmethyl)-4-(4-penzyloxycarbonyl-pentamethylene) xybenzyl]-cundecanedioic acid-pisu (t.

-butyl)-diester (Example 12a) 16.35 J' (16-61 mmol) 14.03.9' (93% of theory) of a colorless oil is obtained.

analysis Calculated value: c62.15 H8,99N7.71 021.14 Measured value: C6 2,01B8.72 N7.78b) 3? 6t 9 9 ) Riaz-3,6,9-) Ri-(carboxymethyl)-4-(4 -Hydondinocarbonylpentamethyleneoxybenzyl)-cundecanniic acid The formulation described in Example 4b ,-butoxycarbonylmethyl-4-(4-hydrazinocarbonylpentamethylene undecanoic acid-bis-(1,-butyl)-diester (e.g. ! L) 6.25 Ji’ (6.88mmol) to white crystal A 3.86.9 (Obtains 87% of the theoretical value. Melting point = 225°C (decomposition) analysis Calculated value: C51,66B6.58 N11.15 030.58 off] Fixed number: C 51,52H6,57N11.20GaPlinicum complex A gadolinium complex is obtained with almost quantitative yield by the method described in Mle. analysis Calculated value: c41.47 B4.89 N8.95 024.55G (B20 ．． 11 Measured value: c41.41 H4,90B9.01G (120,12 Analogous to the formulation described in Example 1e, the following salts are obtained: the sodium salt of the nigar-linium complex Calculated value: C39, 26H4, 39N8.48 023.24G419.04 Na　s,s　6 Measured value: C39, 18B4.33 N8.40Gd 19-00 na 5 -53 Calculated value: c42.00 B6.19 N8.36 o30.02G413 ．． 41 Measured value: c42.10 H6,15N8.33G (113,20 Morpholine salt of gadolinium complex Calculated value: C44,06B5.70 N10.27 023.47ea16.4 8 Measured value: C43,95E[5,71110,23ea16.42 Example 14 a) 3,6,9-triade3,6,9-)ly(1°-butoxycarbonylate) methyl)-4-(4-(methacryloyl)-hydrazinocarbonylpentamethyl) Renoxybenzyl]-cundecanedioic acid-bis(t.

-butyl)-diester 3,6.9-)riad3.6.9-tri(1,-) according to the formulation described in Example 7a. butoxycarbonylmethyl)-4-(4-hydrazinocarbonylpentamethylene oxybenzyl)-undecanoic acid-bis-(t,-butyl)-diester (e.g. 13 a) Colorless oil from 7-78 & (8,56m) 6.02 Calculated value of N (72% of the theoretical value): c62.74 H8,77N7-17 o21.3 measurement value: C62, 511118, 80N7.201+) 3,6, 9-triaz-3,6,9-tri(carboxymethyl)-4-(4-(methac) Liloyl)-Hydrazinocarbonylpentamethyleneoxybenzyl)-Undeca dinic acid 3. By the formulation described in Example 6b. 6. 9-)! j Azo 3.6, 9-) Lee ( 1,-Butoxycarbonylmethyl]-4-(4-(methacryloyl)-hydrazi nocarbonylpentamethyleneoxybenzyl)-U/decanoic acid-bis-(1+ -butyl)-diester (Example 2L) 8 colors from 1-98JF (2-02 mmol) Crystals 1.3EL9 (98% of theory) are obtained.

Melting point: 162°G (decomposed) analysis Calculated value: C53,51E 6.51 1i 10.06 029.89 Measured value :C53,60H6,72N10.100 gadolinium complex By the method described in Example 1e, a gadolinium lead body is obtained with almost quantitative yield.

analysis Calculated value: C43,80B4.98 N8.23 024.47G (118,5 0 Measured value: C43,71H4,81N 8.090418.41 Similar to the recipe in Example 1e, the following salts are obtained: Sodium salt of gallium complex Calculated value: C41.605 4.61 N7.82 023.24 ()d 17. 57 Na s, i 3 turbidity: C41,55H4,62N7.78G417 ．． 50 NIL 5.12 Meglumine salt of gadolinium complex Calculated value: C43,53B6.25 N7.89 029.64G (112,6 6 Measured value: 043.49 B6.27 N7.87ea12.51 Morpholine salt of gadolinium complex Calculated value: C45,78B5.81 N9.58 023.45oa15.36 Measured value: C45,77B5.80 N9.53od1 5.31 fake 15 2L) 3. 6.　　9　−　)　　Ri　　　　・　-3,6,9-) Li-(t,-butoxycarbonylmethyl)-4-(4-(3-(methacrylate) Ruamidocoupropoxy]-benzyl]-undecanoic acid-bis-(1,-butyl )-diester 3,6.9-) by the method described in Example 2a! j Other 3.6,9-tree (1+ -butoxycarbonylmethyl-4-(4-(3-7minoproboxy)-benzyl ]-Undecanoic acid-bis(t-butyl)-diester (Example 9B) Calculated value for 89% of the indicated compounds: C63,69B8.90 1J6.18 021.21 measurement value: C65,61B8.71 N6.22b) 3, 6.9-) rearade 3,6.9-tri(carboxymethyl)-4-(4-(3- (Methacrylamide)-propoxy)-benzylco-undecanedioic acid 3,6.9-triaday 3,6. 9-Tory (1,-butoxycarbonylmethyl)-4-C4-(3-methacrylamide)- propoxy)/<ndil]-cundecanoic acid-bis(t,-butyl)-dieste Starting from Example A, the title compound is obtained with 90% yield.

analysis Calculated value: c53.83 B6.45 N8.95 030.73 Measured value: 0 53.75 B6.25 MB, 60 gadolinium complex The gadolinium complex is obtained with 98% convergence by the method described in Example 1θ.

analysis Calculated value: C43, 17H4, 78N7.19 024.65Ga20.18 Measured value: c43.3D H4,70N7.17oa20.22 GD (AA13): 20.25% The following salt was obtained similarly to the formulation described in Example 1e. Calculated value: C40,87B4.28 N6.80 023.33G419- 11 Na 5.58 Measured value: C40,85B4.23 B6.74Gd 19.01 Na 5. 55 Meglumine salt of gadolinium complex Calculated value: C43, 10H6, 20N7.18 030.07Ga13.43 Measured value: c41.15 B6.19 N7.20Gd13.28 Calculated value: c 45.41 B 5.71 N 8.82 023.52G 416.51 Measured value: C45, 36B5.84 N8.78ea16.39 a) 3,6.9-) Rear day 3. 6. 9-) Lee (1゜-butoxycal (bonylmethyl)-4-(4-carboxymethoxybenzyl)-undecanoic acid- Bis-(1+-butyl)-diester 3.6.9-) Riaday 4-(4-benzyloxycarbonylmethoxybenzyl )-3,6,9-tri(1,-butoxycarbonylmethyl)-undecandyl -pis(1,-butyl)-diester (fllloa) 7.839 (8,43 The formulation described in Example 8a yields a colorless oil of 4.2.9 mmol (theoretical value of 7.0 mmol). 4%) t-obtain.

analysis: Calculated value: c61.62 B8.53 N5.01 024.81 Measured value: c 61.73 H8,53N5.10b)3F6?9) Riazu-3,6,9 -) Lee(1゜-butoxycarbonylmethyl)-4-(4-(2゜3.4, 5.6-pentahydroxyhexyl)-methyla,mino-carbonylmethoxybe undecanoic acid bis-(t,-butyl)-diester 3, 6. 9-) Reaza-3. 6. 9-) Ri-(t , -butoxycarbonylmethyl)-4-(4-carboxymethoxybenzyl)- Undecanoic acid-pis(1,-butyl)-diester 4.56, S'(5 , 4 mmol) in 100 g of Tetto Lahiroff 2, and add triethylamine. Add 0.5 ji (8rn moles). Inject 7 deep tetrahydrof at -5 °C. Chlorformic acid isobutyl ester in Run 40-0.73,! i’ (5,5m mol) t-added, and finally N-methyl-D-glucamine 1.08.9 (5-5 10 d of an aqueous solution of mol) are added. After stirring at 0°C for 30 minutes, remove the cooling bath and bring to room temperature. Heat. After removal of the solvent, the residue was purified by silica sol chromatography. Ru. 4.171 A white crystalline substance that decomposes with a brown coloration above 50°C. 1 (76% of the theoretical value).

analysis: Calculated value: c59.15 B8.53 N5.51 026.79 Measured value: C 59,0758.56 N5.50e) 3. 6. 9-) Li Ata'-3,6,9-tri-(carboxymethyl)-4-[4-(2 ,3,4,5゜6-pentahydroxy-hexyl)-methylamino-carbonyl methoxybenzyl]-undecanedioic acid example 3.6.9-) as described in tetc. ade3゜6.9-)ly(1,-butoxycarbonylmethyl)-4-(j-( 2,3,4,5,6-pentahydroxy-hexyl)-methylamino-carboni [rumethoxybenzyl]-undecanoic acid-bis-(t,butyl)-dieste #3 ．． 259 (3.2 mmol) to the title compound 1.86 with a melting point of 132 °C (decomposition) 9 (79% of the theoretical value) Calculated value: c 49.04 B 6.31 N 7 ．． 62 037.01 Measured value: C49, 191116, 21N7.46 Gadolini um complex Similar to the 1θ formulation, gadolinium complexes are obtained in almost quantitative quantities: analysis: Calculated value: C40,53HA, 87 B6.50 030.59ea17.68 Measured value: C40,72B4.65 1J6.32Gd17.75 Ga (AAs): 17.51 N amount %fl11θ Same as the following recipe Obtain salt: Calculated value: C38,62H4,421J6.00 029.15G (1 16,85Na 4.92 Measured value: C38,68ji4.48 1J5.93G (116,54Na 4 ．． 98 Calculated value: c41.30 B6.06 B6.56 033.7 (SG+11 2.29 Measured value: C41,27B5.98 x6.69Gd11.90 Calculated value: 043.01 B5.60 N7.91 028.64ea14- 81 Measured value: C43,06B5.62 1J7.98Gd14.88 Example 17 a) 3-af-2-(4-benzyloxybendicine-4-ocyneglutarate di Amide (method) O-benzyltyrosinamide 3-629 (13.3 mmol) ethyloxame) 2-7 Ji’ (2373! mol) and dimethod for 14 hours. Boil in a medium stream of xiethane. After removing the solvent, water, ethanol and ether are added in layers. Wash with water. White crystals after drying 2.731! (60% of the theoretical value) is obtained. Melting point = 270℃.

analysis Calculated value: C63,331115,61N12.30 018.74 Measured value: 06 3.24 B5.52 1J12.14 or by method B: α) 6-7day 2-(4-benzyloxybenzyl)-4-;ir+nglutar Acid-5-ethyl ester-1-amide 0-benzyltyrosinamide 3,9 (11-1 mmol) in dimethoxyethane 60 1, add 1.56 g of triethylamine, and add oxalic acid ether ester at 0℃. Luchloride L53. Li' (11.1 mmol is added dropwise. After 30 minutes at 0°C, ice 1 00-Pour on top, sieve and dry. Yield is 3.87 & (theoretical value) 94%).

Melting point: 142°C.

analysis Calculated value: C64,85B5.98 N7.56 021.59 Measured value: C6 4,71H6,111! 7.46β)3-7day2-(4-benzyloxybe 4-oxoglutaric acid-5-ethyl ester-1-amide (example aα) 3.6 & (9.72 mmol) with a solution of 31 mol of NH/l of methanol 40' Pour ILt. After 1 hour the precipitated product is filtered off. Compound 3.13 after drying g (95% of theory) in the form of colorless crystals. Melting point: 269°C.

analysis Calculated value: C63,33E 5.61 1J 12.30 018.74 Measured value :063.25 B5.63 N12.17b) 3-7 Day 2-(4- Hydroxybenzyl)-4-oxoglutaric acid diamide Example - 3-azo-2-(4-benzyloxybenzyl)-4-oxoglutal Acid diamide 111 (2.9 mmol) t-10% palladium-activated carbon 100M9 and a few drops of concentrated hydrochloric acid and methanol 201LtK, and hydrogen until the end of hydrogen absorption. become After filtering off the catalyst, 690 cm of colorless crystals (93% of theory) are obtained. Melting point: 2 45-2509C (decomposition) analysis Calculated value: C52,58B5.21 1J16.72 025.47 Measured value: c5 2.83 B5.19 N175.84C) 3-7day 2-(4-hydro (roxybenzyl)-pentane-1,5-diamine bicyclic acid salt 3-7day 2-(4-hydroxybenzyl)-4-oxoglutaric acid diamide ( Example b) 19 (4.0 mmol) is reacted according to the recipe described in Example 98. profit The colorless crystal obtained was 1.199 (96.7% of the theoretical value).

Melting point = 268℃ analysis Calculated value: C41,61H6,981J13.23 05.03C133,13 Measured value: C41, 60H6, 95113, 170133, 33 d) 3 p6e9 - Tori af-3,6,9-) -butoxycarbonylmethyl)-5-(4-hydroxybenzyl)-undecane diacid-bis-(t,-butyl)-diester 3-azo-2-(4-hydroxybenzyl)-penta -1,5-diamine m = hydrochloride (Example C) 5-19Ji' (16,3 mmol ) to give the indicated compound in the form of a viscous clear liquid 7.759 (theoretical value 61 %).

analysis Calculated value: c63.13 H8,91N5.38 022.56 Measured value: C63 ,00yo8.92　N5.298)　3. 6. 9-) Riazu-5-(4 -benzyloxycarbonylmethoxybenzyl)3,6.9-tri(t, -butylene) Toxycarbonylmethyl)-undecanediruhis-(t,-7'thyl)-die Stell 3.6.9-) ria+l'-3,6,9-) li(t,-butoxycarbo nylmethyl)-5-(4-hydroxybenzyl)-undecanoic acid-bis(t , -butyl)-diester (example eL) 5.0,! i’ (6.4 mmol) t-Reacted with benzyl bromoacetate according to the formulation of Example 6a to form a colorless mucilage. of oil 4.6 & (74.8% of theoretical value).

analysis Calculated value: C64,70118,36N4.52 022.40 Measured value: C64, 46H8, 30N4.49f) 3. 6. 9-) Ri Azo-3 ,6,9-) Li-(carboxymethyl)-5-(4-benzyloxycarboxylic acid) (rubonylmethoxybenzyl)-undecanedioic acid 3, 6. 9-) Li Ad-de-3. 6. 9-) Li-(t,-butoxycarbonyl methyl)-5-(4-benzyloxycarbonylmethoxybenzyl)-kundeca Nionic acid-bis-(1,-butyl)-diester (Example 17e) 3-69 (5-7 mmol) to a white solid 3.9,! according to the formulation given in Example 6b. i’ ( 82% of the theoretical value).

Melting point 145℃ (decomposition) analysis: Calculated value: c55.63 H5,75H6,48032,11 Measured value: C55, 67H5,54116,65 gadolinium complex according to the procedure described in Example 1e. Manufactured from.

analysis: Calculated value: c44.93 H4, 27H5, 24025, 93G419.61 Measured value: c45.01 II4.21 N5.15oa19.70 Gcl (MUAS): 19.61% Similarly to the formulation described in Example 1θ, the following salts are obtained: Sodium of the nigathrinium complex salt Calculated value: C42, 60H3, 81N4.96 024.59G418.59 Ha　5.43 Measured value: C42, 61E 3-82 N A, 90Gd 1 8.40 1 Ja 5.45 Gadolinium complex meglumine salt Calculated value: C44,32B5.74 1J5.87 030.860dl 3.1 8 Measured value: c44.31 H5,59N5.74 ()413.12 Morpholine salt of gallium complex Calculated value: C46, 85H5, 17H7-18024, 63ea 16.14 Measured value: c46.72 H5, 21lJ7.18ea 16.16 Example 18: a) 3,6.9-) rear day 3. 6. 9-) Lee (1゜-butoxycarbo nylmethyl)-5-(4-(3-benzyloxycarbonylaminoproboxy) )-benzyl]-undecanoic acid-bis-(t,-butyl) 3, 6. 9 -) Readay 3. 6. 9 - Tori - (t, - Butoki cyclocarbonylmethyl)-5-(4-hydroxybenzyl)-undecanedioic acid-bi Su(t,-butyl)-diester (Example 17 eL) 9-6 Ji' (5 , 90 mmol) to 4.2 mmol of colorless oil by the formulation described in Example 1b. Only 74%) get t-.

analysis Calculated value: C64, 30B8.51 NS, 76 021.41 Foot value: C6 4-45H8, 55N5.76b) 3. 6.9-) Rear day 3. 6, 9-) ly(1°-))oxycarbonylmethyl)-5-(4-(3-aminoproxycarbonylmethyl) Ropoxybenzyl]-undecanedioic acid-bis-(1,-butyl)-diester By the method described in Example 1c Butoxycarbonylmethyl-544-(3-penzyloxycarbonylaminopropylene) Roboxy)benzyl]-cundecanoic acid-bix-(1,-butyl)-diester (Example a) 2.8 IC1.25 mmol) was hydrogenated. colorless viscous oil get.

Yield: 2.28.9 (95% of theoretical value) Analysis Calculated value: c63.13 B9.15 N6.69 021.02 Measured value: C63, 22B9.14 1J6.66C) 3, 6.9-) Rear day 3, 6, 9 -) Lee(1゜-butoxycarbonylmethyl)-5-(4-(3-(maleimide) -propoxy)-benzyl]-undecanoic acid-bis-(t,-butyl)-die By the method described in Stell Example 1d, 3,6,9-)! j Azor 3, 6, 9-) (1,+,butoxycarbonylmethyl)-5-(4-(3-aminozoloboxybene) ]-cundecanoic acid-bis-(t,-butyl)-diester (Example b) Starting from maleimir, a yield of 90% is obtained (colorless, viscous oil).

analysis Calculated value: C62, 86H8, 35N6-10 022-62 Measured value: C62, 75R8,411J 6.01d) 3,6.9-) rear day 3,6.9-tree (carboxymethyl)-5-[4-(3-(maleimidosoloboxy)-benzi) 3,6.9-)riad6.6°9-t as in Example 1G]-undecanedioic acid li(t,-butoxycarbonylmethyl)-5-(4-(3-maleimido-propyl) xy)-benzyl]-undecanedioic acid-bis(t,-butyl)-diester (e.g. Starting from C), the free pentaacid is obtained as an eight-colored powder with a yield of 96%.

Melting point: 285℃ (decomposition) analysis Calculated value: c52.82 H5,69N8.80 032.67 Measured value: c52 ．． 70 B5.82 N8.74 Gadolinium complex As already described in Example 1e, the gado-17nium complex is obtained in a quantitative yield.

analysis Calculated value: C42,52H4,20N7.08 026.300d19.88 Measured value: c42.39 H4,211i7.19Gd19.55 G(1(AAS): 1 8.63% The following salt was obtained by the formulation described in Example 1e. Sodium salt of Nigarium linicum complex Calculated value: C40, 28B3.74 N6.71 024.910t118.2 3 Na 5.50 Measured values: C40,18B5.87 B6.69Gd13.68Na 5,57 Meglumine salt of gadolinium complex Calculated value: C42,7D H5,85N7.28 030.52Ga13.63 Measured value: C42, 60H5, 70N7-36Gli13.61 Morpholine salt of gadolinium complex Calculated value: C44,89H5,121J8.72 024.91G416.32 Measured value: C44,90B5.11 1J8.63Ga15.98 Similar to the recipe for the production of gadolinium complexes, the following is obtained: indikmu complex Calculated value: C44, 93H4-44N7.49 027.79 engineering n15.34 Measured value: C44,99B4.50 N7.38 work n15-41 Yztrium-complex Calculated value: C46,48B4.59 N7.75 028.75Y 12.43 Measured value: C46, 46B4.48 N7.58Y 12.15 Ytterbium-complex Calculated value: C41,68B4.12 N6.95 025.79Yb21.45 Measured value: C41,75B4.08 N6.92Yb21.32 Samarikmu complex Calculated value: C42,89H4-241J7-15 026.538m 19.18 Measured value: c42.88 B4.36 N7.22am 19.15 praseodymium complex Calculated value: 043.42 H4, 29N7.24 026.86Pr 18.1 9 Measured value: 043.43 B4-24 N7.30Pr18.32 cobalt complex Calculated value: C48,56H4,80N8.09 030.04Co8.51 Measured value: c48.55 H4,49N8.12a) 3. 6. 9-) rear day 3. 6. 9-tri(1゜-butoxycarbonylmethyl)-5- (4-hydrazinocarbonylmethoxybenzyl)-undecanedirubis-(t , -7'thyl)-diester 3, 6. 9-) rear day 5-(4-benzilo (xycarbonylmethoxypenzyl)-3,6,9-)! j-(1,-butoxyca (e.g., 17e) from 15.29 (13,57 mmol) according to the formulation (7) described in Example 4a, A highly viscous oil of 9.69% (83% of theory) is obtained at room temperature.

analysis Calculated value: C60,61H8,63N8.21 022.53 Measured value: C60,4 9H8, 52N8.23b) 3. 6. 9- Tori A'-3, 6, 9-) Li-(carboxymethyl)-5-(4-hydrazinocarbonylmethyl (toxybenzyl)-undecanoic acid 3, 6. 9-) Ri bruise- 3. 6. 9-tri-(t,-butoxy-carbonylmethyl) -5-(4-hydrazinocarbonylmethoxybenzyl)-undecanoic acid-bis -(1+-butyl)-diester (example &) 2.1, li+ (7.9 mmol ) is reacted with trif A-oacetic acid according to the recipe described in Example 4b. White after post-processing Crystals 3.1.9 (67% of theory) are obtained.

Melting point: 180℃ (min ζ) analysis Calculated value: c48.33 H5,87N12.25 033.59 Measured value: C 48,15H5,83N12.31 All gadolinium complexes by the method described in 1e. Manufactured by

analysis Calculated value: C33,06H4,16H9,64026,45G (121,66 Measured value: C32, 97H4, 17H9, 70Gd21.65 oa (aAs): 21.63% Analogously to the formulation described in Example 1e, the following salts are obtained: Sodium salt of gadolinium complex Calculated value: c35.88 H3,66H9,09o24.94G420.42 1Ja5.97 Measured values: C35, 76H3, 68H9, 11G (L 20.19 H&6. Meglumine salt of 00 gadolinium complex analysis: Calculated value: C39,85H5,69MB, 79 031.560 (114,10 Measured value: C39,80H5,721JEL71G414.02 Calculated value: C41,415B5A6 N10.91 024.940d17.5 1 Measured value: C41,51H5,15N10.78Gli17.36 Example 20 a) 3. 6. 9-) Li Azo-3,6,9-) Li- (1°-butoxycarbonylmethyl)-5-(4-benzyloxycarbonylmethyl) (t,-butyl)-undecanni(butyl)-di ester 3,6,9-117 days 3,6,9-)(1,-butylene) by the formulation described in Example 3a. Toxycarbonylmethyl]-5-(4-hydroxybenzyl)-undecanedioic acid -bis-(1,-butyl)-diester (Example 17d) 3.8 & (4-87m mol) to give 3.69.9 (77% of theory) of a colorless oil.

analysis Calculated value: C, lS5.89 H8,70N 4.26 021.13 Measured value :C65,66H8,63H4,38b) 3,6,9-tria f-3,6,9- ) Lee(carboxymethyl)-5-(4-benzyloxycarbonylpentamethyl) Renoxybenzyl)-cundecanniic acid The formulation described in Example 3b butoxycarbonylmethyl)-5-(4-benzyloxycarbonylpentamethyl) Renoxybenzyl)-undecanoic acid-bis-(1,-butyl)-diester (Example &) White crystals 5.51.9 (theoretical) from 8-39 (8.43 mmol) 93% of the value).

Melting point: 186℃ (decomposition) analysis Calculated value: C58,02 6.44 H5,97029,55 Measured value: C58, 09H6,3I n6.03 gadolinium complex The gadolinium complex is obtained in approximately quantitative quantities by the method described in Example 1e.

analysis Calculated value: C47,59H4,931J4.89 024.24Ga18.32 Measured value: C47,70H4,70) 14.82G418.50 Obtain the following salts similar to the recipe described in False 1G: Analysis: Calculated value: C45, 27H4, 47N4.65 023.06G (117-43N a 5.09 Measured value: C45, 30H4, 48N4.62Gtl 17.28 Na 5. 017 Calculated value: C46, 18N6.13 N5.60 029.47oa 12.59 Measurement*: ca6.19 H6,09N5.71G (112,52 Morpholine salt of gadolinium complex Calculated value: C48,9<S N5.67 1J6.79 023.29σd15 ．． 26 Measurement [: C49,03B5.66 N(5,8[]G(115,11 Example 21 SL) 3. 6. 9- Tori Day 3. 6. 9 -)　　　　-(1゜-Butoxycarbonylmethyl)-5-(4-hydrazino carbonylpentamethyleneoxybenzyl)-undecanoic acid-pis-(1,- Butyl)-Geste according to the formulation described in Example 4a, 3,6,9-)! j Azor 3. 6,9-)-(1,-butoxycarbonylmethyl)-5-(4-benzyloxy undecanoic acid-pis-(1, -butyl)-diester (Example 20 SL) 13.05 g (13,26 mm mole) 10.72 N (89% of theory) of a colorless oil is obtained.

analysis Calculated value: C62,25N8.99 N7.71 021.14 Measured value: C62 , 16N9.01 N7.75b) 3t 6t 9-Triade 3, 6,9-)Lee(carboxylmethyl)-5-(4-hydrazinocarbonyl pen tamethyleneoxybenzyl)-lanticandic acid 3,6.9-417 days 3.6,9-) Lee(1,- Butoxycarbonylmethyl-5-(4-hydrazinocarbonylpentamethylene) xybenzyl)-undecanedioic acid-bis(t,-butylcudiester (example a) ) 4.59 (4-95 mmol) to white crystals 2.801i (theoretical value of 90 %).

Melting point = 217℃ (decomposition) analysis Calculated value: C51,66H6,58N11.15 030.58 Measured value: C51 ,49N6.55 1!11.12 Gadolinium-complex The gadolinium complex is obtained in approximately quantitative quantities by the method described in Example 1e. analysis Calculated value: C41,47H4,89B+8.95 024.55G420.11 Measured value: C41,50B4.85 N8.80G420.01 Analogous to the formulation described in Example 1θ, the following salt is obtained: Calculated value: C39,26H4,39N 8.48 023.24Ga 19.04 Ha 5.56 Measured value: c39.18 Ha, 33 N8.40 GeL 19-00 N a 5-53 calculated value: C42,00B6.19 N8.36 030.02G a13.41 Measured value: C42, 10B6.15 N8.33Gti 13.20 Calculated value: C44.06B+5.70 N10.27 023.47G416. 48 Measured value: C43, 95B5.71 Bit O, 23ea16.42 Example 22 &)3,6.9-triade3,6,9-)ly(1゜-butoxycarzanylmethyl) )-5-(4-(methacryloylkuchtnodi7carbonylpentametherene) [oxybenzyl]-undecanoic acid-his-(t.

-butyl)-diester 3,6.9-) according to the formulation described in Example 7a! j Azo 3.6, 9-) Lee (1- butoxycarbonylmethyl)-5-(4-hydrazinocarbonylpentamethylene oxybenzyl)-undecanoic acid-bis-(t,-butyl)-diester (e.g. 21 a) 9.0, li’ (9.9 mmol) to colorless oil 6.58 ．． 9 (68% of the theoretical value) is obtained.

analysis Calculated value: C62-74H8, 77N7.17 021.3 (IIj fixed value: C62 , 63H8, 72N7.21b) 39619) Reazo-3,6,9-to li-(carboxymethyl)-5-(4-(methacryloyl)-hydrazinocal Ponylpentamethyleneoxybenzyl]-undecanedioic acid 3,6,9-) according to the formulation described in Example 6b! jAzo3.6,9-tri(1+- butoxycarbonylmethyl)-5-(4-(methacryloyl)-hydrazinocal) (bonylpentamethyleneoxybenzyl)-undecanoic acid-bis(1,-butylene) )-Diester (Example &)) 2-25,! White crystals form from i' (2-3 mmol) 1.41&(88% of eliii value) is obtained.

Melting point: 139°C (decomposition) analysis Calculated value: c53.51 H6,5i N10.06 029.89 Measured value: c53.52 H6,50N10.13 gadolinium complex The gadolinium complex is obtained in near quantitative quantities by the method described in Example 1e. analysis Calculated value: 043.8D H4,98B8.23 024.47ea18.50 Measured value: c 43.71 H4,86N 8.31G (B18.38 Analogous to the formulation described in Example 1e, the following salt is obtained: Calculated value: C41,60B4.61 1J7.82 023.240dl 7.57 1Ja 5.13 Measured value: C41,61B4.58 N7.80Gd 17.39 Na 5.08 Calculated value: C43,53B6-25 N7.89 029.64oa12.66 Measured value: C43, 53H6, 20N7.88G (B12.45 Morpholine salt of gadolinium complex Calculated value: C45,78B5.81 1J9.58 023.45G415.36 Measured value: c45.79 B5.77 b9.55Ga15.20 Example 23 a) 3. 6. 9-) Liaday 3. 6. 9 -Tri-(1゜-butoxycarbonylmethyl)-5-(4-(3-(meth) tacrylamiton-propoxy)-benzyl]-undecanoic acid-bis-(t, -butyl)-diester By the method described in Example 2a, 31.6. 9-Triade 3,6,9-) Lee ( 1-butoxycarbonylmethyl)-5-(4-(3-aminopropoxybenzyl) ]-Undecanedioic acid-bis-(t,-butyl)-diester (Example 18b) The title compound was obtained as an oil with 86% yield.

analysis Calculated value: c63.69 I (8,90N6.18 021.21 Measured value: C6 3,80B8.74 N6.25b) 6. 6. 9- Tori Ashiichi -3,6,9-) Li-(carboxymethyl)-5-44-(3-(methac) lyl-7mido)-propoxy)-pencil cucundecanedioic acid 3.6.9-) Liadedry(1,-butoxycarzanylmethyl)-5-(4 -(3-(methacrylamido)-propoxy)benzylcosylundecanedioic acid-pi Starting from the su-(1+-butyl)-diester (example a) and the method described in example 2b. Similarly, the indicated compound is obtained with 91% of the station names.

analysis: Calculated value: C53,83B6.45 B8.96 030.73 Measured value: C53 ,78H6,31B8.95 Gadolinium complex The gadolinium complex is obtained in a yield of 98% analogous to the recipe of Example 1e.

analysis: Calculated value: c43.17 B4.78 N7-19 024.65G420. 18 Measured value: C43, 33H4, 60N7.15G (120, 12 Ga (AAS): 20.23% Similarly to the formulation described in Example 1e, the following salts are obtained: Sodium salt of Niga V linium complex Calculated value: C40, 8714-28B6.80 o23.33Ga 19.11 　Na　5.58 Measured value: C40, 88H4, 25N6.78G419-05 Na 5.59 Meglumine salt of gadolinium complex Calculated value: c43.10 II6.20 N7.18 030.070d13 ．． 43 Measured value: 043.01 B6.15'M7.14ea13.40 is the morpholine salt of trinium complex Calculated value: C45,41B5.71 B8.82 023.52Ga16.51 Measured value: C45, 38B5.77 B8-. 80ea16.41 Example 24 &) 3. 6. 9-) Rear day 3. 6. 9-) Lee (1゜- butoxycarbonylmethyl)-5-(4-carboxymethoxybenzyl)-un Decanoic acid-pis-(1+-butyl)-diester 3, 6. 9-) Riaday 5-(4-benzyloxycarbonylmethoxyben) Jill)-3,6,9-)! j-(1+-butoxycarbonylmethyl)-undeca /2-bis=(1,-butyl)-diester (Example 17e) 4.9 g (5-1 6 mmol) to a colorless viscous oil according to the formulation described in Example 8a. 96.2% of the theoretical value).

analysis: Calculated value: C61,62H8,53N5.01 024.81 Measured value: C61, 66EB, 45 N5.15b) 3t 6t 9 9 Liazo-3,6,9-tri-(1゜-butoxycarbonylmethyl)-5 -(4-((2゜3.4,5.6-pentahydroxyhexyl)-methylamino )-carbonylmethoxybenzyl]-undecanoic acid-bis-(t,-butyl) -Diester 3, 6. 9-) Re-a-de-3. 6. 9 -)　　　　　-(t,-butoxycarbonylmethyl)-5-(4-carboxy methoxybenzyl)-cundecanoic acid-bis(t,-butyl)-diester 3 ．． Dissolve 90 g (4.6 mmol) in Tetrahydro7ran 801Lt and add Add 0.431 (6.8 mmol) of ethylamine. Tetrahydrof at -5℃ Chlorformic acid isobutyl ester in run 30-0.629 (4,70m-11 -#) @carefully (add, and finally N-methyl-D-glucamine 920■ (4 Add 10 g of an aqueous solution of -7 mmol). After stirring for 60 minutes below 0°C, remove the cooling bath. Remove and heat to room temperature. After removal of the solvent, the residue was chromatographed on silica sol. Purify by White crystalline substance that decomposes above 50°C with brown coloration3. 739 (80% of theory) t-obtained.

analysis: Calculated value: c 59.15 H8, 53N S, 51 o 26.79 measurement Value: Cs5', is B8.6. OB5.55C) 3. 6. 9 -)　　　Li　A勺”　　　　　　　　　　　　　勺　　-3,6,9-)　　　　　　　　　　-　-　　-(carboxymethyl)-5 -(4-((2,3,4,5゜6-pentahydroxyhexyl)-methylamino )-carbosylmethoxybenzylco-undecanedioic acid 6, as described in Example 1e. 6.9-) Reade-3゜6.9-tri(t,-butoxycarbonylmethyl) -5-(4-((2,3,4,5,6-pentahydroxyhexyl)-methyla (mino)-carbonylmethoxybenzyl]-undecanoic acid-bis-(t,-butyl Table of melting point 132°C (decomposition) from 1.77.9 (1.7 mmol) -diester Calculated value for the following compound 1.04FC (83% of the theoretical value): c 49-04 1 < 5 ．． 31 x 7.62 o 37.01 Measured value: C49, 12H6, 35N 7.50 Gadolinium complex A gadolinium complex with a convergence of 98% is obtained analogously to the formulation of Example 1e.

analysis: Calculated value: C40, 53H4, 87N6.30 030.59Gd17.68 611j Fixed A [: c 4 0.6 1 H4, 71M 6.3 　5Gd17.92 ea (AAs) 17.86% by weight Analogous to the formulation described in Example 1e, the following salts are obtained: Analysis: Calculated value: 038.62 H4,42N6.00 029.15Ga 16.8 5 H & 4.92 Measured value: C38,57II! 4.43 N6.03G416.54 1ia 4.88 Meglumine salt of gadolinium complex Calculated value: c41.3D H6,061!6.56 033.76G (L12. 29 Measured value: C41,17B5.98 1J6.59 Calculated value: C43,01B5.6 0 N7.91 o28.64G (L14.81 Measured value: C42,96B5.52 17-97oa14.85 Example 25 a) 3. 6-siade6,6-bis-(1+-butoxycarbonylmethyl ) -4-C4-(2-7'ropynyloxy]-benzylco-sperinic acid-bis -(1+-butyl)-diester Sodium hydride (80% in paraffin) in Dorol 501 690 ■ (13 , 3 mmol) in 20 rLt of 3,6-diade 3 ,6-bis-(t,-butoxycarzanylmethyl)-4-(4-hydroxyben Zyl)-speric acid-bis-(1,-butyl)-diester (Example 1 a) 3 ．． A solution of 77 g (6-05 mmol) and 3-bromp in doluol 20- Add dropwise a solution of Lopin 750 (6.3 mmol). After 2 hours, wash with water. After evaporating and concentrating the silica sol, it is subjected to chromatography. Oily substance 3.029 (75.5% of the theoretical value) is obtained.

analysis: Calculated value: c65.43 B8.54 N4.23 021.78 Measured value: C 65,33B8.60 N4.30b) 3.6-diaz-3,6-bis-(ka (ruboxymethyl)-4-[4-(2-propynyloxy)-benzylco-spere acid 3.6-dia+)'-3,6-pisu(1,-butoxycarbonylmethyl)-4 -C4-(2-7'rovinyloxy)-benzylco-speric acid-pis-(t, -Butyl)-diester 1.35&(2 mmol) was reacted according to the recipe described in Example 1e. make them respond. White powder (740 ■, 83% of theory) which dissolves with decomposition at 140 °C ].

analysis: Calculated value: C5!5.04 B5.54 N6-41 032.99 Measured value: c55.13 B5.59 N6.40 Gadolinium complex The gadolinium complex is obtained as described in 1θ.

analysis Calculated value 2c40.76 B3.58 N4.74 024.37Gd26- 62 Measured value: c40-80 B5.60 y4.70G (126,36 Analogous to the formulation described in Example 1e, the following salts are obtained: Calculated: c39.21 B3.2 9 N4.57 o23.50G425.66 1Ja 3.75 Measured value: c39.22 B3.22 N4.60G425.36 NSL 3.74 Calculated value: C41,2 (S R4,87N5.34 o28.50GcL20 ．． 00 Measured value: C41, 22B4.89 N5.32G, 120.31 Calculated value: c42-59 H4, 31N6.20 023.64G+123-2 3 Measured value: c42.48: B4.30 N6.15G (L 23.15 Example 26 &) 3. 6. 9-Tori Day 3. 6.　　9　 -) Lee(1゜-butoxycarbonylmethyl)-4-(4-(2-propylene) nyloxy)-benzyl]-undecanedioic acid-bis(1+-butyl)-dies ter3.6,9-)riaz-3,6,9-)ly(t,-butoxycarbonylmethane) t,-butyl)-4-(4-hyroxybenzyl)-undecanedioic acid-bis(t,-butyl) )-diester (Example 9f) 5-3611 (6,87m%) Dissolve in Qd and carefully add sodium hydride 363j'9 (15,1 rnn moles) Add. Add to this 3-bromopropyne 858Xv (7-2m mol) dropwise.

After 2 hours, the bath liquid is stirred for tIL, the organic phase is washed twice with water and the solvent is removed. silica Colorless oil by gel chromatography 4.89.9 (87% of theory) ).

analysis: Calculated value: C64,60H8,741J5.13 021.51 Measured value: C64, 57B8.64 N5.15b) L 6.　　9　　　　) Af-3,6,9-) Li-(carboxymethyl)-4-(4-(2- propynyloxy)-benzyl]-undecanedioic acid 3. 6. 9-) Azo-3,6,9-tri-(t,-buto (oxycarbonylmethyl)-4-[4-(2-propynyloxy)-benzyl]- Undecanoic acid-hyx-(t,-butyl)-diester 4.35, li’( 5-32 mmol) are reacted according to the recipe described in Example 1e. Under decomposition at 142℃ A white powder (2,42In9, 85% of theory) is obtained which dissolves.

analysis: Calculated values: c 53.62 B 5.81 N 7.81 032.74 measurement Fixed value: C53,66B5.85 N7.82 gadolinicum monocomplex The gadolinium complex is obtained as described in 1e.

analysis: Calculated value: C41,<57 B4.07 N6.07 025.44Ga22 ．． 73 Measured value: C41,42114,121J6.27G (122,59 Sodium salt of the nigathrinium complex similar to the formulation described in 1e to obtain the salt Calculated value: C39,18B5.56 N5.71 023.92 (M21.3 7 lJ & 6.24 measurement gIL: C38,97B3.55 N5.65 023.90Gd 21.53 Na 6-25 Meglumine salt of gadolinium complex Calculated value: C42,17B5.77 N6.47 031-040a14.53 Measured value: C42,01B5.63 N6.50 030.98ea14.55 Calculated value: C44,48B5.13 N8.10 024.07oa18.20 Measurement 1 shift 2 C44,51!5.08 N8.12 024.10G ( 118, [ ] N a) 3. 6. 9-) Li Azo-3,6,9-) Li (1°-butoxycarbonylmethyl)-5-(4-(2-propynyloxy)- benzyl]-undecanoic acid-bis(1,-butyl)-diester 3, 6 ．． 9-) Re-a-de-3. 6. 9-) Ri-(t, -butoxycarbonylmethyl)-5-(4-hyroxybenzyl]-undecane Niacid-bis-(t,-butyl)-diester (Example 17d) 4.57. ! i'(5 , 8 mmol) 1i - sodium hydride 310 and 3 as described in Example 26a. - React the title compound using Bromopropyne 730M9. colorless oil and and convert the indicated compound into 4-. Obtained in a yield of 0.07.9 (74% of theory).

analysis: Calculated value: C64,60B8.74 N5.13 021.51 Measured value: C64 , 64H8, 70N520b) 39 6. 9-) Lia f-1 ,6,9-) Lee(carphokidimethyl)-5-[4-(2-7'rovinyl oxy)-benzyl]-cundecanniic acid 3. 6. 9-) Lia'-3,6,9-Tori-(t,- butoxycarbonylmethyl)-5-C4-(2-frovinyloxy)-benzyl Co-undecanoic acid-bis(1,-butyl)-diester 4-699 (5,7 mmol) are reacted according to the recipe described in Example 1e. Dissolves under decomposition at 135℃ , a white powder is obtained.

-Analysis: Calculated value: C53,62B15.81 N7.81 032-74 Measured value: 05 3.66 B5.90 N7.75 Gadolinium complex The gadolinium complex is obtained as described in 10.

analysis: Calculated values: c41.67 B4.07 N6.07 025.44Gd22. 73 Measured value: C41,66H4,11N6.04Gd22.51 Analogously to the formulation described in Example 1e, the following salts are obtained: mu salt Calculated value: c39.18 B3.56 NS, 71 023.92 Gd21. 37 Nl! L6.24 Measured value: C39,3211!3-55 B5.80 023.81 (M21 ．． 50　Na-6,27 Meglumine salt of gallium complex analysis: Calculated value: C42,17B5.77 N6.47 031.04G+114.5 3 Measured value 2c42.15 Hs, 6o N6.51 031.05ea14. 37 Morpholine salt of gadolinium complex Calculated value: C44,48B5.13 N8.10 024.07oa18.20 Measured value: C44,45B5.15 N8.11 024.170 (118,1 9 Example 28 a) 1l-(4-(N, N, N', N'-tetrakis-(t, -but Toxycarbonylmethyl)-2,3-diaminopropyl-phenoxyacetyl )-aminoundecanoic acid-(2-(t,-butoxycarbonyl)-hydrazide] 3,6-diaf-3,6-bis-(t,- butoxycarbonylmethyl)-4-(4-carboxymethoxybenzyl)-spe Phosphoric acid-bis-(t,-butyl)-diester (fl18a) 18.2311 (26,78 mmol) and triethylamine 2-7.9 (26,8 mmol) Chlorgi dispersion in tetrahydrofuran with constant cooling below 5 °C to a solution of A solution 3[]d of 5-65 IC26,8 m-v-le) is added dropwise to the butyl ester.

30 minutes after the end of the addition (during further cooling and stirring) gradually add the 11-amino Undecanoic acid-2-(t,-7'toxycarbonyl)-hydrazi r8.44.9 Add a solution of The mixture is then heated to room temperature while stirring to evaporate the solvent. residue was placed in Doruol 400- and the water-soluble components were extracted with saturated saline solution. washing with water After cleaning and drying, the solvent was removed and the oil was chromatographed on silica sol. Subject to further refinement. In this way, colorless oil 20.1.9 (theoretical value 79 %) is obtained.

analysis: Calculated value: 063.19 B9.22 N7.36 020.2 Measured value: C 63,17B9.25 N7.31b) 11-(4-CIJy LN ',N'-tetrakis-(carboxymethyl)-2,3-diaminopropyl-2 phenoxyacetyl)-aminoundecanoic acid hydrazide The t,-butyl ester was prepared using trifluoroacetic acid as described in Example 1e at room temperature. Separate with Under this condition ii (4C’y Ny”v N’-tet Rakis-(t,-butoxycarbonylmethyl)-2,3-diaminopropyl-2 phenoxyacetyl)-aminoundecanoic acid-(2-(t,-butoxycarbonyl) )-hydrazide] to separate the t,-butoxycarbonyl-protecting group of acid hydrazide. and 7 from starting material 12.56, F (13.2 mmol) in the manner described in Example 1e. A 7.3% harvest yielded 6.68"g of white crystalline material, which decomposed at 115°C. Start dissolving at the bottom.

analysis: Calculated value: C55,11B7.24 N10.71 026.92 Measured value: C5 4,98117,30N10-77 gadolinicum monocomplex Calculated value: C44,59B5.48 1!8.66 021.78oa19.46 Measured value: C44,55B5.49 N8.71G (119,21 Sodium salt of the nigathrinium complex similar to the formulation described in 1e to obtain the salt Calculated value: 043.41 B5.22 N8.43 021.20G418. 94 1Na 2.77 Measured value: c43.36 B5.19 N8.47Gd-18,59Na 2 ．． 76 Meglumine salt of gadolinium complex Calculated value: C44, 30H6, 12N8.57 025.51oa15.67 Measured value: c 44.33 H6, 15N 8.51Gti 15.76 Morpholine salt of gadolinium complex Calculated value: C45, 67H5, 86N9.39 021.47G (Li2.58 Measured value: C45,77H5,801J9.28ea17.38 Example 29 a) 11-(-<4-(4-(t,-butoxycarbonylmethyl)-4-7 De2,6-di[bis-(1゜-butoxycarbonylmethyl)-7mino]-he xyl〉-phenoxyacetyl)-7minoundecanoic acid-[2-(t,-butoxyl) cyclocarbonyl)-hydrazide] 3, 6. 9- Tori Day 3 ．． 6. 9-) Li-(t,-butoxycarbonylmethyl)-4- (4-carboxymethoxybenzyl)-undecanoic acid-bis-(t,-butylc) -diester (Example 16a) 8-4.9 (10 mmol) was prepared according to the recipe of Example 28a. amounts of triethylamine, chloroformic acid inbutyl ester and 11-7 minun React with decanoic acid-2-(t,-butoxycarbonyl)-hydronsite. Kara Colorless oil by muchromatography NH 8.74.9 (77% of theoretical value) ) exists Calculated value: C62,40H9,05N7.40 021.13 Measured value: C 62-31H9,10N7.36b)11-(4-(4-(carboxymethyl) -4-af-2,6-di[bis-(carboxymethyl]-amino]-hexyl 〉-phenoxyacetyl)-aminoundecanoic acid hydrazide 1l-(4-<4-(t,-butoxycarbohydrate) as described in Examples 1e and 28). nylmethyl)-4-7z-2,6-di[bis-(t,-butoxycarbonylmethyl) tyl)-7mino]-hexyl>-phenoxyacetyl)-aminoundecanoic acid- (2-(t,-butoxycarbonyl)-hydrazide) 6.32,! i’ ( With a yield of 76%, the title compound is obtained in the form of colorless crystals.

Melting point: 185℃ (decomposition) analysis: Calculated value: C54, 10H7, 21N11.13 027.55 Measured value: C53, 98H7,23N11.10 Gadolinium-complex analysis: Calculation ([:C44,92I(5,,65N9.24 022.870d17.2 9 Measured value: c4495 H5, 60N9.26G417.33 Analogous to the formulation described in 1e, two analyzes yielding the following salts: Calculated value: c42.85 H5, 18N8.81 021.82G (L 1 6.50 1Ja 4.82 Measured value: c42.69 H5, 12N8. 80G4 1 6.25 1ia 4.83 Meglumine salt of gadolinium complex Calculated value: c44.36 H6,59N8.62 028.31oa 12.1 0 Measured value: c44.35 H6,50N8-63 Calculated value: C46,65H6,2 4Nl0-36 022.19G (115,54 Measured value: C46, 66H6, 30N10.24ea15.32 Example 60 a) 11 (4<3-((t-butoxycarbonylmethyl)-6-ade )-2-((bis-(1,-butoxycarbonylmethyl)-aminoco-methyl) -5-[bis-(t,-butoxycarbonylmethyl)-aminoco-pentele] phenoxyacetyl)-aminoundecanoic acid-[2-(t,-butoxycarzani) )-hydrazide] 3. 6. 9-) Lia No.'-3, 6, 9-) Li-(t, -butoxycarbonylmethyl)-5-(1-carboxymethoxybenzyl)-u Ndecanoic acid-bis-(t,-7'thyl)-diester (Example 24a) 6.1 3 g (7.3 mmol) were mixed with an equivalent amount of triethylamine, Rolformic acid isobutyl ester and 11-aminoundecanoic acid-2-(t,-butyl ester) (oxycarbonyl)-hydrazide. The essence of column chromatography Colorless oily substance: l', 04 # (85% of theoretical value) calculated value: C62 ,4H9,05N7.40 021.13 Measured value: C62,31H9,17N 7.56b) 11-(4-<3-((carboxymethyl)-3-azoE- 2-CCbis-(carboxymethyl)-aminoco-methyl)-5-[bis-(carboxymethyl)-aminoco-methyl) (ruboxymethyl)-aminoco-pentyl>-phenoxyacetylnoaminoun Decanoic acid hydrazide 11-(4-<3-((t,-butoxycarbonylmethyl-6-ab)-2-C (bis-(1-butoxycarbonylmethyl)-7/]-methyl, l-5-(bis-(1-butoxycarbonylmethyl)-7/]-methyl, Su-(t,-butoxycarbonylmethyl)-7mino]-pentyl>-phenoxy Acetyl)-aminoundecanoic acid-(2-(t,-butoxycarbonyl)-hydro [Razide] 5.389 (4.7 mmol) to flille and the treatment described in 28b. By this method, colorless crystals of 2.93% (82% with only 82% fill-in) were obtained. Melting point = 19 2°C (decomposition) analysis: Calculated value: C54,1B7.21 N11.13 027.55 Measured value: c5A , 09 B7.28 N11.11 Gadolinicum monocomplex analysis: Calculated value: C44,92B5.65 N9.24 022.87oa17.29 Measured value: c44.80 B5.66 N9.22G417.03 Analogously to the formulation described in 1e, the following salt is obtained: Calculated: C42,85B5. 18 N8.81 021.820d l 6.50 H&4.82 measurement Value: C42,88B5.12 N8.83Gd 175.91 lJ & 4 ．． Megurumi/salt of 88 gadolinicum complex Calculated value: C44,36B6.59 1J8.62 028.31Ga 12.1 0 Measured value: C44, 32H6, 30N8.71G (112, 12 Gadolinium-complex heptulfol/salt analysis: Calculated value: c4s, 2s H6, 24N1o, s6022.190d15.54 Measured value: c46.39 B6.26 N10.32Gd15.61 Example 61 a) 3,6-diade3,6-bis-(1+-butoxycarbonylmethyl)-4 -(4-oxiranylmethoxy)-benzyl-speric acid-bis-(t,-butyl )-diester 3.6-diade3,6-bis-(1+-butoxycarbonylmethyl)-4-( 4-Hydroxybenzyl)-speric acid-bis-(t,-butyl)-diester (Example 1 a) 80% hydrogenation of 17-38F (27.9 mmol) in paraffin Add 900 μg (30,711 mol) of sodium and 300 μg of dolol while stirring. Dissolve and add dropwise a solution of epichlorohydrin 2-6 & (28 mmol) at 40 °C. . After 1 hour, carefully add 100μ of water. After drilling, the phase is separated, followed by the organic phase. Concentrate after drying. 15-5F as a colorless oil by chromatography (22.8 mmol, 82% of the theoretical value) exists Calculated value: C63,69B8.61 N4.12 023.56 Measured value: C63,57H8,62N4.07b) 15-(4-(y, N, 19', N'-tetrakis-(to-butoxy) cyclocarbonylmethyl)-2,3-diaminopropyltwophenoxy)-12-7 14-Hydroxy-pentadecanoic acid-2-(butoxycarbonyl)-hydra Jido 3,6-siade6,6-bis-(t,- butoxycarbonylmethyl)-4-(4-oxiranylmethoxy)-benzyl- Speric acid-bis-(1+-butyl)-diester 7.35!1 (10,8 m mole) 11-aminoundecanoic acid-2-( Add 3.411 (10.8 mmol) of t,-butoxycarbonyl)-hydrazide. Then, heat with distant current for 2 hours. After removal of the solvent, the material is analytically a thin-framed, colorless oil. It exists as. Yield 9.54 g (88.5% of theory).

analysis: Calculated value: C62,81B9.22 N 7.04 02 [1,91 elevation J Value: C62,65B9.23 H7,15c) 15 i 4 (Ny "t"? “”-Tetrakis-(carboxymethyl)-2,3-diami Nopropyltwophenoxy)-12-az-14-hydroxy-pentadecane powder Hi V Rajid 15-(4-(2y 3-n, N, n', n'-tetrakis- (t,-butoxycarbonylmethyl)-2,3-diaminopropyltwophenol ci)-12-azo-14-hydroxy-pentadecanoic acid-[2-(butoxycal) (bonyl)-hydrazide) 4.36 & dissolved in trifluoroacetic acid 5ON at room temperature and work up for 5 hours as described in Example 1e. Colorless crystal 2-867i (3 −2 mmol; 73% of theory) is obtained.

Melting point: 145℃ (min.) analysis: Calculated value: c55.59 B7.62 N10.45 026.27 Measured value: C55,60B 7.49 N 10.55 Gadolinium-complex: Calculated value: c45.18 B5.87 N8.49 021.35oa19. 08 Measured value: c45.2D I! 5.88 N8.62Gd19.09 Analogously to the formulation described in Example 1e, the following salt is obtained: Calculated: C44,01B5. 59 N8.27 020.800d l 8.58 H&2.71 measurement Value: 043.95 B5.61 N3-230418.38 N&2. 77 Meglumine salt of gadolinium complex Calculated value: C44, 82H6, 55N8.25 028-140a15.44 Measured value: C44,69B6.46N 8.20oa15.40 Calculated value: C46-24H6,091J9.24 021.11oa17.29 Measured value: c46.23 B6. ii B9.282L) 3. 6. 9-tri azo-3,6,9-) ri-(1゜-butoxycarbo nylmethyl)-4-(4-oxiranylmethoxybenzyl)-undecanoic acid- Bis-(t,-butyl)-diester 3. 6. 9-) Re-a-de-3. 6. 9-) Li -(t,-butoxycarbonylmethyl)-4-(4-hydroxybenzyl)- Undecanoic acid-pis-(1,-butyl)-diester (Example 9f) 16.35. 9 (21-On mol) in sodium hydride (80% in paraffin) 630 * (2 1 mmol) in Dorol 300 Tri with stirring, and heated to 40°C. Add a solution of 1.95 and (21 mmol) of epichlorohydrin of all 20 pieces. . Colorless oil after work-up as described in Example 31a 15.4F (88% of theory) occurs.

analysis: Calculated value: 063.20 118.80 1J5.02 022.96 Measured value: C 63,35H8,76N5.09b) 15-4-[4-Aza-2,6-Riamitsu -N.

N, N', N', N'-pentakis-(1,-butoxycarbonylmethylene) )-hexyl]-7dinoxy12-az-14-hydroxy-pentadecane ff1-(2-1,-butoxycarbonyl)-hydrazide anhydrous diethyl ether 3,6°9-triade 3,6.9-tri(1+-butylene) dissolved in 100- (oxycarbonylmethyl)-4-(4-oxiranylmethoxybenzyl)-unde Canniic acid-bis(t+-butyl)-diester 7-51 (9, Ommol) 11-aminoundecane &-(2-1+-butylene) in anhydrous Tetrifuran 501 Add 2.85.9 (9-Om mol) of carbonyl)-hydrazide and bring to reflux. Heat for 2 hours. Colorless oil after removal of solvent and chromatography on silica gel 9.12,! ? (88% of the theoretical value) is obtained.

analysis: Calculated value: C62,58B9.27　H7,29020,84　Fixed value: C62 , 83B9.30 1J7.28c) 15-(4-C4--7day 2,6- Ria Mitsu N.

1'l, N', N', N'-pentakis-(carboxymethyl)- hexyltwophenoxy)-12-af-14-hydroxy-pentadecane- The title compound was prepared at 165° C. in 80% yield as described in Hydracite Example 1e. It is obtained in the form of white crystals with a melting point (decomposition) above .

analysis: Calculated value: C5,! , 53 11! 7.58 N10.90 026.88 measurement Value: C54,62B7.48 1J10.88 gylinium complex Calculated value: c45.44 B5.99 B9.08 o22.48ca 6.99 Measured value: c45.38 H6,02B9.05Cd16.76 Analogously to the formulation described in Example 1e, the following salt is obtained: Calculated: C43,38B5 ．． 51 y8.67 021.460d l 6.22 Na 4.74 measurement Fixed value: 043.42 B5.49 N8.70G416.03 Na 4 -77 Calculated value: c44.80 B6.67 N8.53 028.010 (ill , 97 Measured value: C44,84H6,70B+8.51G (111,88 Calculated value: c47.15 only 6-34 n10.23 021.9101i1 4.35 Measured value: c47.14 H6, 201J10.25oa14.50 a) 3. 6. 9-t rear day 3. 6. 9-) Lee (1゜-buto (oxycarbonylmethyl)-5-(4-oxiranylmethoxybenzyl)-unde Canniic acid-bis-(t,-butyl)-diester Analogously to Example 32a, the title compound is 82% removed from the compound described in Example 17cl. Calculated value as a colorless oil: C63,2D H8,80N5.020 22.96 Measured value: C63,15H8,691J4.93b)15-(4-(3 -7d3-(t,-butoxycarbonylmethyl)-2-[[bis-(t,-butoxycarbonylmethyl) Toxycarbonylmethane-amino]-methyl)-5-[bis-(t,-butoxy) cyclocarbonylmethyl)-7mino]-pentyl>-phenoxy)-12-7de1 4-hydroxypentadecanoic acid-[2-(t,-butoxycarbonyl)-hydro Rajid The title compound was prepared as a clear oil with 81% yield as described in Example 32b. Obtained from the compound described in Example 33a.

analysis: Calculated value: C62,58B9.27 1J7.29 020-84 Measured value: C62 , 47B9.30)J7.30c) 15' (4<3-7day 3-( carboxymethyl)-2-CCbis-(carzoxymethyl)-aminoco-methyl )-5-(bis-(carboxymethyl)-aminoco-pentyl>-phenoxy) -12-azo-14-hydroxy-pentadecanoic acid hydrazide as described in Example 320 The title compound was obtained as a colorless oil in 83% yield from the compound described in 32b. Calculated value obtained with: C54,53B7.58 N10.90 026.88 Measured value : C54,60B7.55 N10.95 Gadolinium-complex: Calculated values: c45.44 B5.99 B9.08 o22.48G (11 6,99 Measured value: C45, 43H5, 70N 9.21G417.01 The sodium salt of the nigatrinium complex is obtained similarly to the formulation described in 1θ. Calculated value: C43, 381115, 51N8.67 021.460 (L 16. 22 Na 4.74 Measured value: 043.45 B5.30 B8.76G (115,90MA 4.75 Meglumine salt of gadolinium complex analysis: Calculated value: c44.80 H6,671J8.53 028. []lGd11. 97 Measured value: C44,95H6,66N8.50oa11.51 Morpholine salt of gylinium complex Calculated value: c47.15 H6,34N10.23 021.91oa14. 35 Measured value: c47.16 B6.32 N10.31Gd14.39 Example 34 a) 3,6-diade2,7-thioquine-4-(4-hydroxybenzyl)-su Peric acid-diethyl ester 1.2-diamino-1-(4-hydroxybenzyl)-ethane-disalt salt 23 g (96.4rnmol) in anhydrous tetrahydrofuran (Tap) 300M 21.4 g (212 mmol) of triethylamine in the solution and stirred at 50°C for 1 hour. After 5-10°C triethylamine in THF2QQag 21.4. li'(2 12 mmol) t-oxalic acid ethyl ester chloride (28,96,!F, 212 mmol) of the cooled solution are added t-drops. After the addition, the mixture was further stirred at room temperature for 1 hour. Heat to reflux for 5 minutes to evaporate the solvent. Dollar all 500! ltK suspended, Toru The bottom is washed with water and the organic phase is dried and concentrated again. Pure raw material to match analytical values The product remains in the form of colorless crystals with a yield of 86% (33.9#).

Melting point = 176℃ (decomposition) analysis: Calculated value: C55,73H6,05N7.64 030.56 Measured value: C55,6 116,15N7.63b) 3. 6-diade 2,7-thioxo 4-( 4-Hydroxybenzyl)-speric acid-diamide 3,6-diade 2,7-cy Oxo 4-(4-hydroxybendiJL/)-speric acid-diethyl ester 17.32.9 (47.2 mmol) was reacted with amyl by the method described in Example 17β. make them respond. A yield of 98% was obtained as white crystals, which turned brown above 285°C. Melts under color.

analysis: Calculated value: c50.64 B5.23 N18.17 025.94 Measured value: C50,66IE5.20 18.23C) 3,6-diade1,8-diamino -4-(4-hydroxybenzyl)-octane (hydrochloride) 3.6-diade 2, 7-thioxo 4-(4-hydroxybenzyl)-sperine diamide 6.16 ．． 9 (20 mmol) was suspended in 200 mmol of anhydrous TEF, and diborane ( NaBH322-6Ji' and boron trisulfide-ether)20517) Conducts a gentle flow while stirring it. Boiled under reflux for 96 hours and then boiled for 96 hours. Introduce half of the original amount of water and boil for another 2 days. Then as described in Example 9e Post-process the sea urchin. The yield was 5.65 N of colorless crystals (71% of the theoretical value), It decomposes above 90°C.

analysis: Calculated value: c39.36 B7. tl 1J14.12 04.03C135 ,36 Measured value: C39,42B7.13 N14.03C135,31 (1) 31　6,9t　12-tetraazo-3,6,9゜12-tetrakis- (1,-Butoxycarbonylmethyl)-7-(4-hydroxybenzyl)-tet Radecanedicarboxylic acid-bis-(t,-butyl)-diester 3.6-diade1,8-diamino-4-(4-hydroxybenzyl)-octa Tetrahydrochloride 13.219 (33.1 mmol) Labrom vinegar 9t, -7-Tyl ester 36-7, S’ (198-6 mmol) and NaHCO317,211 ( 204.7 mmol) and 500 g of dimethylformamide to the formulation described in Example 1a. Further reaction gives a colorless oil 26.119 (84% of buried la value).

analysis: Calculated value: C62,79B 9.03 2J 5.97 022.19 Measured value: C62,78B8.87 1J5.96li 3,6,9.12-tetraazo-3 ,6,9゜12-tetrakis-(1+-butoxycarbonylmethyl)-7-C4 -(3-amino)-propoxybenzylco-tetradecanedicarboxylic acid-bis- (1+=butyl)-diester The 4-hydroxybenzyl compound obtained in d) was prepared according to the formulation described in 1b. Alkylate. The product obtained in this way (in 72% of vehicles) was not isolated. to be used in the next reaction step (amine-protecting group separation according to the recipe described in 1C).

The title compound was obtained as a pure colorless oil with a yield of 82% and consistent analytical values. It will be done.

Analysis: Calculated value: C62,75H9,31N7.03020.89 Measured value: C 62,7D H9,28127,13t)3,6,9.12-tetraaz-3, 6,9,12-tetrakis-(carboxymethyl)-7-C4-(3-7mino) -Propoxy-benzylco-tetradecanedicarbone alcohol Ester 2-56 obtained by a). li’ (2-5 mmol) with trifluoro Stir in 30 d of acetic acid (anhydrous) at room temperature for 2 hours. Then pour into ether 3QQILt Filter with suction, suspend twice with 100 i of ether each and dry. colorless crystals 1.4# (85% of theoretical value) remains.

Melting point = above 135℃ (min%) analysis: Calculated value: C51,13H6゜59　N10.64　031.62 Measured value: c 51.25 H6,62N10-50 gadolinium complex as described in 1e d obtained by Gatrinium complex: Calculated value: c41.42 H4,96y8-62 025.61ca19.36 Measured value: C41,53H5,011J8.39ca19.09 Analogously to the formulation described in 1e, the following salts are obtained: mu salt Calculated value: c38.31 H4, 24147-97023, 69()d 17. 91 Na 7.85 Measured value: C38, 25H4, 11x7.56G418. 05 Na7.86 Meglumine salt of gadolinium monocomplex Calculated value: C42, 11H6, 56H8, 01032, 05G (Lll, 25 Measured value: C42, 25H6, 70H8, 09oa11.13 Example 35 3. 6. 9-) Li Azo-3,6,9-) Li-(Carbo xymethyl)-4-(4-[3-(melimido]-propoxy]-benzyl)- Undecaniic acid and Fab-7 fragment of monoclonal antibody 7B10DI1 111 indium complex of conjugate of a) Production of F(ab')2-fragment: Antibody 7B10D11 16m' 9 (100 nmol) in 0.1 m acetate buffer (FJ(4,5) and 0.1 M The mixture was dissolved in 11 Lt of saline solution and incubated at 37 °C for 20 min after the addition of 0.3 μl of pepsin. Maintain constant temperature for an hour. -7,0 Ultraderm cA44 (Firma LKB ) through ff preparation and lyophilization, the desired fragment 6.3■ (theoretical value 63%) is obtained.

7-ragment ko obtained by a), IM-phosphate buffer (pH 6,0) 14.5m of 0.1M mercaptoethylamine solution and 0.1M of mercaptoethylamine solution. ．． Ethylenediaminetetraacetic acid 15% in 1M phosphate buffer (pH 6,0) It dissolves upon addition of mmol. After keeping the temperature at 67℃ for 2 hours, it was placed under argon protection. Separate through a 5 ephadex G 25-column. Measurement of sulfhydryl groups 268 nmol of SR groups are obtained in the reaction batch at a constant temperature.

0.7 μmol (2.15 μmol) of the complexing agent described in Example 9j was added to 0.1 m-phosphoric acid. Dissolve in 10 ml of salt buffer (pH 6,0). This was prepared as above at 4°C. Add the solution of F’ab-7 fragment, and shake gently overnight (maximum 4℃] Allow to react. It was then eluted through a cation exchanger and 0.1 m-acetic acid Dialyze against ammonium solution and lyophilize. 14.1μ of white powder was obtained. It will be done. Buffer 111 nC13-solution (pH 5,583mci/rd) 1g solution (20 mmol of sodium acetate; 150 mmol of sodium chloride) in 25 ILt. Add to the conjugate solution and keep at constant temperature for 4 hours. Then further IC0.1m sodium acetate Add 51 Lt of solution, dialyze and freeze dry.

13.82 ml of white powder with a specific activity of 5 m C1/lll& is obtained.

Example 36 Monoclonal antibody 7B10DI 1 and 15 (4-[4-7day 2,6-dia Mitsu N, N, N', f, N'-pentakisu (carboxymethyl) -hexylcyphenoxy)-12-7de-14-hydroxy-pentadecanoic acid 1ll-indium complex of conjugate with human 2cyto 30 nmol of antibody was pre-equilibrated in 0.1 m sodium acetate buffer (-5). , and in a column protected against light ingress by an aluminum sheet , combined with a macroporous strongly acidic cation exchanger. Then periodic acid in the eluent Rinse with 0-03 m sodium periodate in acetate buffer until salts form. . Interrupt the rinse for 30 minutes, then wash with acetate buffer, then wash with the above hydrazide (Example 32) of 0-037ZL and sodium cyanoborohydride 0.1 m, resulting in a solution. After 2 hours, the complexing agent is removed. Elute with acetate buffer and conjugate with a saline gradient. After desalination, freeze-drying let 4.5 kg of conjugate as described in Example 65 was obtained, which was llindicumu complex.

Example 37 a) N-carbobenzoxyserine-(2-carbobenzoxyaminoethyl Ren)-amide Acid ethyl ester, triethylamine and N-(2-7minoethyl)-carba React with benzyl minic acid ester-hydrochloride and work up. colorless crystals 10.3 39 (81%) are obtained.

Melting point: 167°G analysis: Calculated value: C60,71H6,06N10.11 023.1 Measured value: C60,7 5N5.98 1J10.15b) (2-7minoether)-serine amyl N-ka Rubobenzoxyserine-(2-carbobenzoxyaminoethylene)-amide 13.46#”t methanol 200111 in 10% palladium-activated reconstituted 1.3 In the presence of 71, 7KX is hydrogenated until it is no longer absorbed. Filter out the catalyst , all volatiles are removed with an oil pump. Partially crystalline oil of V2 Note Things remain.

Yield 4.67.9 (98%) analysis: Calculated value: C40,8D H8,89N28.55 021.74 Measured value: C 40,71H8,85N 28.30C) 1-hydroxymethyl-1,3, 5-) Liadepentane trihydrochloride Similar to the formulation of Example 9e, the title compound was obtained as a white product from the above amide in 67% yield. It is obtained as a crystalline powder.

Melting point: 266℃ (decomposition) analysis: Calculated value: C24,75N7.47 N17.32 06.59C143,84 Measured value: C24,71N7.50 nl 7.41C'143.98 a) 4-hydroxymethyl-3,6,9-triade 3, 6. 9-) Ji -(1,-butoxycarbonylmethyl)-undecanoic acid-di-t. -butyl-di Similar to the formulation of ester example 1a, (ether/hexane-1) was prepared with a yield of 78%. /2) The listed compound is a colorless oil. Obtained as an object.

analysis: Calculated value: C59,71N9-31 N5-97 025.0 Measured value: C59, 66N9.32 N5.99e) Gadolinium complex or its salt in Example 1θ Obtain as described.

Calculated value: C42,55B5.95 N9.92 041.56 Measured value: C43 ,08B5.88 N9.73 Calculated value: C30,04N3.53 1J7.0 0 029.35Ga 26.22 Na 3.83 Measured value: C30, 51B 3.55 N 7.04G426-22 1J & 3.88 Calculated value: C31,19N3.83 N7.27 030.46()(127, 22 Measured value: C31, 70N3.84 N7.21G (127-36 Example 38 a) Bis-1,414-<2.6-di[bis-(1,-butoxycarbonylmethane) [Tyl]-7mino]-4-(t,-butoxycarbonylmethyl)-azo-hexame tyrene〉-phenoxy) ~ pig/ 4-(4-hydroxybenzyl)-3,6,9-)riad3.6.9-)di (1+-butoxycarbonylmethyl)-undecanoic acid-bis-(t,-butyl )-diester (Example 9f) 13-7 g (17,56 mmol) was added to anhydrous doluol. (10011j), 530 g of NAH (80% suspension in paraffin) Carefully add 1 g (17.6 mmol) and heat to 40-50° C. for 10 minutes.

It was then cooled to 0°C and dibromobutane 1.91 (8,8 mmol) is added. Raise the temperature to room temperature, then continue heating to 80-100°C for 30 minutes. Ru. Chromatography on silica sol after removal of solvent and f11 treatment through glass wool. Apply to graphics. In this way colorless oily substance 10-5! ! (6.5m model 74% of the theoretical value).

analysis: Calculated value: C63,99H8,99lJ5.2 C21-8 Measured value: C64, 57N9.11 N5.18b) Bis-1,4-(4-<2.6-G [Bis (carboxymethylcou-amino)-4-(carboxymethyl-7-dehexamino) Tyrene〉-phenoxy)-butane The free complexing agent was prepared as described in Example 1e with a yield of 73% and a melting point of 228°C (minutes). Solution] Calculated value obtained in the form of white crystal: C52,46N6.12 N7.98 C33,42 measurement value: C52,I H6,12N8.05 gallinium complex and its salts are obtained quantitatively as described in Example 1θ.

Gd-complex Analysis: Calculated value: C40, 58H4-29N6.17025.85 Gd 23 ．． 09 Measured value: C40, 21H4, 32N6.18Gd23.32 Sodium salt of Gd-complex Analysis: Calculation *: c 39.31 n 4.01 y 5.97025. 04 Na 3.27 G422-37 foot value: C38,91B3-94 N6.08Na 3.31 G422.11 Analysis 2 calculated value: C41,48B5.92 1J6.53031.36 0d l 4.68 Measured value: C42, 27B5.84 1J6.47Ga14.62 Example 39 a) N, 2N'-bis-f4-(3-(t,-butoxycarbonylmethylene) )-azo-5-bis-(t,-butoxycarbonylmethyl)-amino-2-bis su-(t,-butoxycarbonylmethyl)-aminomethyl]-pentamethylene- 7 dinoxyazeteru) hydrazide in 250 ILt of tetrahydrofuran at 0°C. 5-(4-(carboxymethoxy)-benzyl)- prepared with water exclusion 3,6,9-) Liazu'-3,6,9-) Li-(1,-butoxyca (e.g., 24a) A-18,5' (4,99 mmol) and triethylamine and Rolmi 1? A solution of an equimolar amount of the acid isobutyl ester was gradually added to the solution with further cooling. Tetrahydro 7 run 501! LtcP hydrazine 74M9 (2-49 mmol ). 1 hour at 5°C, another 1 hour at room temperature and 3 hours at 45°C. After stirring for 0 minutes, cool, concentrate and take up the acetate. m=after, water and 0 ．． Wash several times with 1N hydrochloric acid. Finally, clean with silica sol using ether/hexane. Apply romatography. A colorless oil of 3.179% (76% of theory) was obtained. It will be done.

Analysis: Calculated value: C61,77H8,55N6.7022.96 Measured value: C62, 26H8, 52N6.61b) N, N'-bis-+ 4-(3-(carboxymethyl)-a-5-bis-(carboxymethyl)-a Mino-2-bis-(carboxymethyl)-7minomethyl]-pentamethylenephene (oxyacetyl)-hydrazide The formulation described in Pseudo 1e produced a free complexing agent with a yield of 78% with a melting point of 250°C (minutes). Obtained as a white powder of Song.

Analysis 2 calculated value: C49,72...5.62 N10.08034.56 Measured value: C49,77B5.67 N10.03 Gado IJ nium complex and The salt is obtained quantitatively as described in Example 1e.

Analysis: Calculated value: C38,92yo 3.97 N7.89027.05 G(i 22.15 Measured values: c 38.71 B 3.91 N 7.87G (122,34 G(1- Sodium salt of the complex Analysis: Calculated value: c 37.75 B 3.71 1J 7.65026.2 3　Na　3.14　G421.49 Measured value: c37.82　B5.70 N7.72NIL 3.09 Ga 21.13 N-methyl of G4-complex glucamine salt Analysis: Calculated value: c40.39 1i5.68 N7.63031.99 G cl　14.29 Measured value: c40.56 B5.70 y7.54G414.13 Example 40 ! L) 1,12-bis-4-(3-(t,-butoxycarbonylmethyl)-7de -5-bis-(1,-butoxycarvinylmethylcouamino-2-bis-(t, -butoxycarbonylmethyl]-7minomethyl]-pentamethylenephenoxy- 4,9-lua f-5,8-dioxo-dodecamethylene 5-[:(4-3 -aminopropoxy)-benzyl]-3,6,9-)di(1,-butoxycal) (bonylmethyl)-3,6,9-)riadeundecanoic acid-bis(1+-butyl )-diester (Example 18b) 8.36 Ji’ (9.99 mmol) at 0°C. 770 μ (4.96 mmol) of succinic dichloride are carefully added dropwise. after that, Heat to reflux briefly, filter, wash the organic phase thoroughly with water, and chromatize on silica gel. Apply to tograph. Finally, a colorless oil 7.62, F (82% of the theoretical value) ) is obtained.

Analysis: Calculated value: C62,92B9.05 N7.48020.52 Measured value: C61,93B8.95 N7.56b) 1,12-bis-4-( 3-(carboxymethylar)-5-bis-carboxymethyl)-amino-2 -bis-(carzoxymethyl)-7minomethyl-pentametherene-phenoxy) -4,9-Diadedioxododecamerene As described in Example 1e, the free complexing agent is obtained with a yield of 78%.

Melting point: 220℃ (decomposition) Analysis 2 calculated value: C53,20H6,77NICL69029.32 Measured value: C52,82H6,801J10.76 gadolinium complex and its is obtained quantitatively as described in Example 1e.

aa-complex Analysis 2 calculated value: C43,05115,I N8.65023.73 G(1 19,45 Measured value: c43.28 B5. I N8.74Ga19.51 Analysis: Calculated value: c41.92 H4, 85118, 42023, 10Ha 2.76 G (118-92 measurement value: C42, 63H4, 81lJ 8.2 8Na 2.71 G (118-57 G(N-methylglucamine salt analysis of L-complex: Calculated value: C43,06H6,30 N8.17029.34 Gd l 3.11 Measured value: 043.91 B6.19 N8.290413.06 Example 41 a) 3. 6-siade6,6-bis-(1,-butoxycarbonylmethyl )-4-(4-(3-(5-<2-oxo-2,3,3a,4,6.6a-hex sahydro-1'B-cheno-(,3,4-4)imidazol-4-yl>-vale lylamino)-propoxy)-benzylco-sperate-bis-(t,-butyl ) - Dies ° Chill N-Hydroxysuccinimir-biotin (Piercecha IC, Comp, ) 6,6-dia in DMlF 6m+7 to 341.41n9 (1 mmol) De3,6-bis-(1,-butoxycarbonylmethyl)-4-(4-(3-7 minoproboxy)-benzylcosperic acid-bis-(t,-butyltudies) (Example 1c) Add 679.9 - (in mol) t - Stir overnight. Continuation The reaction solution is evaporated and chromatographed on silica sol (dolol). /glacial acetic acid/ethyl acetate/methanol-6:4:4:3).

Combine the pure fractions by thin layer chromatography, evaporate the solution in vacuo, and Dry over OH. Yield: 695■ (78% of theoretical value) Analysis: Calculated value: C60, 97H8, 54N7.73019.24 83.54 Measured value: C61,05H8,29N7.7183.30 b) 3,6-siade6,6-bis-(carboxylmethyl)-4-(4-(3 -(5-<2-oxo-2,3,3a,4,6,6a-hexahydro-IH-thi Eno-(3,4-cl)imidazol-4-yl>-valerylamino I-propo [oxy]-benzylcosperic acid Compound 41a Add 3d of trifluoroacetic acid to 453■ (0-5 mmol), Stir for 0 minutes. Subsequently, precipitation was performed with anhydrous diethyl ether, and the precipitate was dissolved in diethyl ether. Wash with water and dry. Yield: 298~ (90% of theoretical value) Analysis: Calculated value: c52.85 B16.40 N10-27025.81 sa, 70 Measured value: C52,79H6,49N10.2084.59 The gadolinium complex is prepared according to the procedure described in Example 1e.

Analysis 2 calculated values: C43.10, B4.82 1J8.38021.05 83. 84 0d 18.81 Measured value: c43.01 B4.79 N8.45f 33.97 Ga 18.47 Example 42 a) 5,6,9-)ria f-4-(4-hydroxy/zyl)-3,6,9-to Li(carboxymethyl)-undecanedioic acid 3.6.9-) Riaday-4-(4-hydroxybenzyl)-3,6,9-) (1,-Butoxycarbonylmethyl)-undecanoic acid-bis(t,-butyl )-Diester (Example 9f) 7.80 g (10 mmol) Wotrifluoro/I-acetic acid 1 00at, and after 1 hour precipitated with diethyl X-thyl. Ethanol/concentrated Purification after chromatography on silica sol in ammonia/water (8:1:1) The separated fractions were passed through Amberlite U120 (H”), and the dispersive eluate was frozen. Let dry.

Yield: 4.09.9 (82% of theory).

Analysis: Calculated value: c50-50 B5-85 N8.41 Measured value: C50,3 9EI5.85 N8.34b) 3# 6,9) Rear day 4-(4 -hydroxybenzyl)-3,6,9-tri(carboxymethyl)-undeca Nni Air 0.501 (17a%/') of the lead acid described in Example 42a was added to a 40111K bath of water. Add 181% of Gd20s (0-5 mmol) and heat at 80℃ for 30 minutes. Stir for a minute, filter, and lyophilize the filtrate. Yield: 0.65 N (theoretical value 99.4%] Analysis and calculation value: C38,58B4.01 y6.43026. 92　G424.06 Measured value: c38.39 H4,02y6.47G (124,11 What is for in-vivo NMR diagnosis? Display of gallbladder and intestinal tumor on machine spin tomography HT29 colon with subcutaneous transplantation 4 Nude mice with (4-hydroxypennol)-3,6,9-tris-( Cal? ximethy/1/)-cadolinium complex of cansoic acid (Example 42) 0.1 mmol/5+ was administered intravenously.

Spin-echo-see fence ( Photographed using T-wing = 400 ms, T-wing = 30 ms). Inspection by General Elec 2 Tesla (T ealm) It was carried out using a nuclear spin tomography machine.

The figure shows three acquisitions; one before and two after administration of the contrast agent. Gallbladder, administration 30 After a minute it clearly contrasts with the surrounding liver tissue. Tumors disappear immediately after administration Showing signal enhancement in the marginal area, while after 30 minutes clear signal throughout the tumor An increase is observed.

Figure: Cross section of a nude mouse in the area of liver and subcutaneous tumor (right side).

Imaging sequence spin-echo (TR = 400 ms, TE = 30 ms).

The upper left is a photograph taken before contrast agent administration, the upper right is a 1-minute diameter photograph, and the lower right is a 30-minute back shadow.

international search report “1111＾　　　　””　PCr/DE　8B100199-Uchi Ichishi I　A- 1-1w KT/DE 8B100199 International Search Report Garbage εε00199 international search report Dmi8aOO199 SA 21454 Continuation of page 1 ■Int, C1,’ Identification symbol Internal reference number Author Krieger, Ehritzg Utrasee, Federal Republic of Germany 5 [Phase] Inventor Niedbara, Ulrich Federal Republic of Germany 　nah Frequent luminaries Renetske, Franz Josef Federal Republic of Germany a Frequent cases Conrad, Jürgen Frequent cases in the Federal Republic of Germany Reverend Mützzel, Wolfgang Federal Republic of Germany + D-10 00 Berlin 30 Augsburger I D-1000 Berlin 33 Goslarstra + D-4709 Belfkamen Hotshostra l D-1000 Berlin Material Sonnenallee-701D-1000 Berlin Wedsdeigenveke

Claims (15)

[Claims] 1. General formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, n and m are numbers 0, 1, and 2, respectively. , 3 and 4, and X is a hydrogen atom and/or atomic number 21-29, 31, 32, Represents the metal ion equivalent of elements 37-39, 42-44, 49 or 57-83 , R1 and R2 are different and each contains a hydrogen atom or one or several imino-, fluorine-containing Phenyleneoxy, phenyleneimino, amide, hydrazide, ester group , one or several hydrocarbons which may contain oxygen, sulfur and/or nitrogen atoms. oxy-, mercapto-, imino-, epoxy-, oxo-, thioxo- and/or is a linear, branched, saturated or unsaturated terminal position which may be substituted with an amino group. General formula IA or IB: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IA) ▲ Mathematical formulas, chemical formulas, etc. There are scientific formulas, tables, etc.▼The second molecule of (IB), the functional group, or the bond via this functional group. represents a C0-C20-alkylene group with combined bio- or macromolecules, but n and m together are not greater than 4, and X represents the metal ion equivalent; with the condition that at least two of the substituents X represent this compound and its salts with inorganic and/or organic bases or amino acids. 2. 2. The compound according to claim 1, wherein X is a hydrogen atom. 3. At least two of the substituents X have atomic numbers 21-29, 42, 44 or 57-8 at least one element of 3 or atomic number 27, 29, 31, 32, 37-39, at least one radionuclide of the elements 43, 49, 62, 64, 70 or 77 2. A compound according to claim 1, which is a metal ion equivalent. 4. R1 represents a hydrogen atom, and R2 represents one or several imino-, phenylene- or xy, phenylene imino, amide, hydrazide, ester group, oxygen, may contain sulfur and/or nitrogen atoms, one or several hydroxy, Mercapto-, imino-, epoxy-, oxo-, thioxo- and/or amino -NH2;-NHR;- as a functional group at the terminal position which may be substituted with a group; NHNH2, -NRNH2, -SH, -OH, -COCH3, ▲ mathematical formula, chemical formula, There are tables, etc.▼;▲There are mathematical formulas, chemical formulas, tables, etc.▼;▲Mathematical formulas, chemical formulas, tables, etc. There are▼;-C≡C-C≡CR;▲There are mathematical formulas, chemical formulas, tables, etc.▼;-C 6H4CH2Br;▲There are mathematical formulas, chemical formulas, tables, etc.▼;-CH2Br;-CH 2J;-COCH2Br;-CH=CH-CH2Br;▲Numerical formulas, chemical formulas, tables, etc. Yes▼;-O-SO2-C6H4CH3;-SO2Cl;-SOCl;▲number There are formulas, chemical formulas, tables, etc. ▼; ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; ▲ Mathematical formulas, There are chemical formulas, tables, etc.▼;▲There are mathematical formulas, chemical formulas, tables, etc.▼;▲Mathematical formulas, chemistry There are formulas, tables, etc.▼;▲There are mathematical formulas, chemical formulas, tables, etc.▼;-C≡CH;▲Number There are formulas, chemical formulas, tables, etc. ▼；-CH2CONHNH2, ▲Mathematical formulas, chemical formulas, tables, etc. There are ▼-CH2CO2CH2C6H5; ▲There are mathematical formulas, chemical formulas, tables, etc. S▼；(CH2)10CONHNH2 [In this case, R and R1 are the same or different, and each is a hydrogen atom, saturated or unsaturated, a C1-C20-alkyl group or a phenyl group substituted by a phenyl group 2. A compound according to claim 1, which represents a C0-C20 alkylene group having the following formula. 5. R2 represents a hydrogen atom, R1 represents one or several imino-, phenylene oxy- -, phenyleneimino, amide, hydrazide, ester group, oxygen, sulfur may contain yellow and/or nitrogen atoms, one or several hydroxy, Mercapto-, imino-, epoxy-, oxo-, thioxo- and/or amino -NH2; -NHR; -N as a functional group at the terminal position which may be substituted with a group; HNH2;-NRNH2;-SH;-OH;-COCH3;▲Mathematical formula, chemical formula, table There are ▼;▲There are mathematical formulas, chemical formulas, tables, etc.▼;▲There are mathematical formulas, chemical formulas, tables, etc. Yes▼;▲There are mathematical formulas, chemical formulas, tables, etc.▼;-C≡C-C≡CR;▲Mathematical formulas , chemical formulas, tables, etc. ▼；-C6H4CH2Br；▲ Numerical formulas, chemical formulas, tables, etc. Yes▼;-CH2Br;-CH2J;-COCH2Br;-CH=CB-C H2Br; ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; -O-SO2C6H4CH5; -SO2Cl; -SOCl; ▲There are mathematical formulas, chemical formulas, tables, etc.▼;▲Mathematical formulas, chemistry There are formulas, tables, etc.▼;▲There are mathematical formulas, chemical formulas, tables, etc.▼;▲Mathematical formulas, chemical formulas, There are tables, etc.▼;▲There are mathematical formulas, chemical formulas, tables, etc.▼;▲Mathematical formulas, chemical formulas, tables, etc. There are▼;-C≡CH;▲There are mathematical formulas, chemical formulas, tables, etc.▼;-CH2CO NHNH2, ▲There are mathematical formulas, chemical formulas, tables, etc.▼;-CH2CO2CH2C6H 5;▲There are mathematical formulas, chemical formulas, tables, etc.▼;(CH2)10CONHNR2 [In this case, R and R1 are the same or different, and each is a hydrogen atom, saturated or unsaturated, a C1-C20-alkyl group or a phenyl group substituted by a phenyl group 2. The compound according to claim 1, which represents a C0-C20-alkylene group with thing. 6. A claim in which R1 represents a hydrogen atom and R2 contains a biological or macromolecule. 1. The compound described in 1. 7. A claim in which R2 represents a hydrogen atom and R1 contains a biological or macromolecule. 1. The compound described in 1. 8. The biological or macromolecule contained in R1 or R2 is an antibody, an antibody-fragment with avidin-biotin antibody or avidin-biotin-antibody fragment. A compound according to claim 1, which is. 9. General formula I': ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I') [In the formula, n, m and X are as stated in claim 1. R1' and R2' are those listed for R1 and R2. but without biological or macromolecules] and inorganic and/or organic compounds. Bases or their salts with amino acids. 10. at least one physiologically tolerable compound according to claims 1 to 9. Pharmaceutical preparations containing together with excipients commonly used in galenic medicine. 11. Preparation of drugs for NMR-, X-ray-, radio-diagnosis or radio-therapy use of at least one physiologically tolerable compound according to claim 3 for the production of . 12. At least one physiological compound according to claim 9 as a hapten for antibody production. The use of compounds of general formula I' which are tolerated in 13. General formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, n and m are numbers 0, 1, and 2, respectively. , 3 and 4, and X represents a hydrogen atom and/or atomic number 21-29, 31, 32 , 37-39, 42-44, 49 or 57-83. and R1 and R2 are different, and each is a hydrogen atom or one or several imino-, Phenyleneoxy, phenyleneimino, amide, hydrazide, ester radicals, may contain oxygen, sulfur and/or nitrogen atoms and may contain one or several hydrogen atoms. droxy, mercapto, imino, epoxy, oxo, thioxo and / or straight chain, branched chain, saturated or unsaturated, which may be substituted with an amino group, General formula IA or IB at the terminal position ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IA)▲There are mathematical formulas, chemical formulas, tables, etc.▼ The second molecule of (IB) has a functional group or a macromolecule bonded via this functional group. represents a C0-C20-alkylene group, where n and m together represent more than 4; and when X represents a metal ion equivalent, at least two of the substituents and inorganic and/or organic bases or To prepare its salts with amino acids, in a manner known per se, the general formula II: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, n and m are as above. , R1' and R2' are different and each contains one or more hydrogen atoms or optionally imino, phenyleneoxy, phenyleneimino, amide, hydrazide -, ester groups, oxygen, sulfur and/or nitrogen atoms, optionally 1 one or several hydroxy-, mercapto-, imino-, epoxy-, oxo-, Straight-chain, branched, saturated or unsaturated, substituted by thioxo- and/or amino-groups General formula (I'A) or (I'B) at the terminal position of the sum: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I'A)▲There are mathematical formulas, chemical formulas, tables, etc. ▼Represents the second molecule of (I'B) or a C0-C20-alkylene group having a functional group. and R3 represents a C1-C6-alkyl group], and thus The resulting acid of general formula II' in which R3 represents a hydrogen atom, if desired, a) By a method known per se, atomic numbers 21-29, 31, 32, 37-39, 42- Reaction with at least one metal oxide or metal salt of elements 44, 49 or 57 to 83 and subsequently, if desired, replace the azide hydrogen atoms present with inorganic and/or by substitution with organic bases or cations of amino acids, or b) by methods known per se. , atomic number 21-29, 31, 32, 37-39, 42-44, 49 or 57- reacting with at least one metal oxide or metal salt of 83 elements and subsequently The metal complex thus obtained is incorporated into R1' or R2' by a method known per se. bond to biological or macromolecules through functional groups present and, if desired, Replacement of azido hydrogen atoms by inorganic and/or organic bases or amino acid cations or c) Generate via the functional group contained in R1' or R2' by a method known per se. atomic number 21-29, and subsequently in a manner known per se. At least of the elements 31, 32, 37-39, 42-44, 49 or 57-83 reacting with one metal oxide or metal salt and subsequently, if desired, reacting with one metal oxide or metal salt. The azide hydrogen atom is replaced by an inorganic and/or organic base or an amino acid cation. A process for producing a compound of general formula I, characterized in that: 14. Coupling of macromolecules to functionalized complexes or ligands as well as to ligands In the case of coupling, the following complexation is carried out using one or several desired metal ions: 14. The method according to claim 13, wherein the method is carried out in a stationary phase. 15. The complex compound may be dissolved or suspended in water or saline solution, as the case may be. Formed into a form suitable for intestinal or parenteral administration with additives commonly used in Galenic medicine. , A method for producing the O formulation according to claim 10.