JPS635077A - Physiologically tolerable complex compound, manufacture and radiodiagnostic and radiotherapeutic drug - 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 Field of Industrial Application The present invention relates to a novel complexing agent, a complex and a process for producing the complex salt, and a drug containing the same for radiodiagnosis and radiotherapy.

BACKGROUND OF THE INVENTION Complexes or their salts have long been used in medicine, for example as auxiliaries for the administration of recalcitrant ions (e.g. iron) and for detoxification in the case of accidental doses of metals or their radioactive isotopes. as an antidote (in this case calcium- or zinc complexes are preferred).

European Patent Organization (BP) No. 71564, European Patent Organization (GP) No. 130934, and West German Patent Application Publication (DE-O8) No. 3401052. Complexes and complex salts of aumite are newly developed as diagnostic agents. As, mainly NMR-
It has been proposed as a diagnostic agent.

All complexes and their salts known hitherto give rise to problems with respect to compatibility and/or selectivity of binding and/or stability during their clinical use. The more product derived from the complexing agent is to be administered, the more significant m becomes during these times.

For example, in the treatment of metal poisoning, the insufficient renal tolerability of the compounds available today as well as their tendency to bind abundant ions in the body limit their use.

Heretofore, the use of elements useful in their own right as components of parenterally administered X-ray contrast agents has been frustrated by the insufficient tolerability of such compounds. Nuclear ST
For the paramagnetic, contrast-enhancing substances previously proposed or tested for imaging tomography, the interval between effective doses and toxic doses in animal studies is relatively narrow, and/or it may have little organ specificity and/or or exhibit stability and/or contrast-enhancing effects.

Problems to be Solved by the Invention Therefore, a need arises for a variety of purposes, especially for complex compounds that are better tolerated, but also stable, well soluble and sufficiently selective. .

Means for solving the problem By the way, the anion of the complex-forming acid and the atomic number 21-2
9.61.62.38.39.42-44.49.57
Complex compounds consisting of a central ion of ~70 or 77 elements and optionally one or more physiologically tolerable cations of inorganic and/or organic bases or amino acids can surprisingly
It has been found that it is suitable for the production of medicaments suitable for use in NMR, X-ray, ultrasound- or radio-edge-diagnosis and radiotherapy.

-Form I: [wherein X represents the radicals -COOY and PO3I (Y), where Y represents a hydrogen atom, a metal ion equivalent and/or an inorganic or organic base or a physiologically acceptable amino acid or C00R1
2-group, R6 being a saturated, unsaturated, straight-chain or branched or cyclic hydrocarbon radical having up to 16 C-atoms, which may be substituted by 1 to 5 hydroxy groups; or represents an aryl group or aralkyl group which may be substituted by one or several C1<,-dialkylamino groups or one or several 01<6-alkoxy groups, R7 is a hydrogen atom, 1 to 5 represents a saturated, unsaturated, straight-chain or branched or cyclic hydrocarbon group having up to 16 C-atoms which may be substituted with 1 or 1 hydroxy groups, or R6 and R7 together represent 1 or Several C5-C5-alkyl-1C1-5-hydroxy-alkyl-11 C2<6-acyl-, hydroxy-, carbamoyl-, carbamoyl which may be hydroxylated or Cl-C5-alkoxylated - Substituent color to base color carbamoyl-1 substituted by (can also form a ring with an oxygen atom) or one C1<5-acylamino- or substituted by an alkylacylamino group and another nitrogen-1 acid R12 has 16 saturated, unsaturated, straight-chain or branched-chain or cyclic hydrocarbon radicals having up to C-atoms, in which B represents a macromolecular radical and R1 represents a hydrogen atom or a CH2X- group;
R2 and R3 represent a (CH2)In- group, in which m
is 0 or 11! -, in this case R4 and R6 each simultaneously represent a hydrogen atom, and R' and R5 are CH
2-CH-(CH2)m- group, where m represents O or 1, R8 represents a hydrogen atom or R9, where R9 is an imino, phenyleneoxy, phenyleneimino, amide, or ester group. , straight-chain or branched, saturated or unsaturated, which may contain one atom of oxygen, one sulfur and/or one nitrogen, and which may be substituted by hydroxy, mercapto, imino and/or amino groups. , represents a C1-C20-alkylene group having one functional group or one macromolecule B bonded via it in the terminal position, in which case R2 and R3 simultaneously each represent a hydrogen atom; When v2 is a C0B- group, R8
represents a hydrogen atom, and when X represents a group PO3HY, yl and v2 similarly represent PO, HY].

The elements of the abovementioned atomic numbers which form the central ions of the physiologically acceptable complex salts may of course be radioactive for the desired purpose of use of the diagnostic agent according to the invention.

If the agent according to the invention is intended for use in N'MR-diagnostics (European Patent Organization patent application 6)
The central ion of the complex salt must be paramagnetic. This is especially true for original character numbers 21-29.
They are divalent and trivalent ions of elements 42.44 and 57 to 70. Suitable ions include, for example, chromium(1)-, manganese(If)-1iron(1)-1iron(■)-, cobalt(
■)-, nickel (■)-1 copper (Il)-, zoraceodymium (I)-, neosim (1)-, samarium (1)- and iterbium (1)- ions. Owing to their extremely strong magnetic moments, trinium(1)-, terbium(1)-, dysprosium(1)-, holmium(1)-1 erbium(1)- and iron(I)- ions are particularly advantageous. be.

If the medicament according to the invention is intended for use in X-ray diagnostics, the central ion must be derived from an element of higher atomic number in order to achieve sufficient absorption of the Rentden radiation. For this purpose, diagnostic agents have been found suitable which contain physiologically acceptable complex salts with central ions of elements with atomic numbers between 57 and 70: and the aforementioned ions of the lanthanide series.

The agents according to the invention which are intended for use in NMR diagnostics are also suitable for use in ultrasound diagnostics.

For the use of the agents according to the invention in nuclear medicine diagnostics and therapy, the central ion must be radioactive. For example, radioactive isotopes of the elements copper, cobalt, gallium, dermanium, iterbicum, strontium, indium, iterbicum, dolinicum, samaricum, iridium and especially technetium (Tc-99,m) are suitable.

Aryal substituents R6, R7 and R12 can be saturated, unsaturated, straight-chain or branched or cyclic hydrocarbons with up to 16 C-atoms, in particular saturated with 1 to 10 C-atoms. Suitable hydrocarbons, in particular saturated hydrocarbons with 1 to 5 C atoms, are substituted in the case of R6 and R7 by 1 to 5, in particular 2 to 4 hydroxy groups. has been done. Examples include: methyl, ethyl, zorobyl, isoprogyl, dithyl, isobutyl, pentyl, cyclopentyl,
cyclohexyl, propenyl group.

Suitable hydroxyalkyl groups include, for example: 2-hydroxypropyl-16-hydroxyprot-1, 1-(hydroxymethyl)-ethyl-1.
2*3-dihydro.

xizolovir-, tris-(hydroxymethyl)-methyl-12,3-dihydroxy-1-hydroxymethylprozalyl, 2,3.4.5.6-pentahydroxyhexyl and especially 2-hydroxyethyl-12-hydroxy -1-(hydroxymethyl)-ethyl-12,3-dihydroxyzorobyl- and 2,3.4-)lihydroxybutyl groups.

When R7 represents a hydrogen atom, R3 may optionally be 1
f by one or more C1<6-dialkylamino- or by one or several C1-c6-alkoxy groups
It is also possible to represent lit-substituted aryl or aralkyl groups, for example phenyl or benzyl groups.

The 5- or 6-membered heterocyclic ring formed by R6 and R7, including the amide nitrogen, may be saturated, unsaturated and/or substituted, optionally containing one nitrogen-1 oxygen-
Contains one sulfur atom or one carbonyl group.

Heterocycle includes one hydroxy-11 01<6-alkyl group, e.g. methyl-, ethyl-, propyl-, isopropyl-, butyl group, one cl<5-hydroxyalkyl group, e.g. hydroxymethyl- , by a hydroxyethyl group, or optionally one hydroxy- or 0
It may be substituted by one C,-C6-acyl group, for example an acetyl-, progionyl group, which may be substituted by a 1-C6-alkoxy group, for example a methoxy-, ethoxy group.

Other substituents include carbamoyl groups, which are attached to the heterocycle directly or separated by one C1-C,-alkylene group, such as a methylene-, ethylene-, prozalene group; and optionally 1 or 2 C
1-C,-alkyl groups, such as methyl-, ethyl-, zolotyl, isoprogyl groups (which optionally form a single mass, e.g. a zalolidine- or giberidine-ring)
is replaced by nitrogen. The carbamoyl nitrogen may be a component of the sulfoline ring.

Other possible substituents on the heterocycle include optionally C
1-C,-alkylated or C1-C,-acylated, -class or secondary amino groups, such as methyl-, ethyl-,
Examples include acetyl- and propionyl-amino groups.

Suitable heterocycles include, for example, the following: gyrollidinyl, gyperidyl, birazolizonyl, gylorinyl, pyrazolinyl, piperazinyl, morpholinyl, imidazolidinyl, oxidezolidinyl, thiazolidinyl rings.

The alkylene group contained in R9 may be linear, branched, cyclic, aliphatic, aromatic or arylaliphatic,
and has up to 20 carbon atoms. Preference is given to straight-chain mono- to hexamethylene radicals and also to 01<4-alkylenephenyl radicals.

If the alkylene group contains one phenoxy group, this preferably corresponds to -CH- of the basic skeleton of the compound of general formula I.
is bonded to the group in the p-position through one methylene group.

Advantageous functional groups present at the end of the R9-alkylene group are
For example, benzyl ester, ethyl ester, 1t-butyl ester, amino-1C1-C,-alkylamino, aminocarbonyl, hydrazino, hydrazinocarbonyl, maleimide, methacrylamide, do,
methacryloyl hydrazinocarbonyl, maleimidamide carbonyl, halogeno, merka 7'to, hydrazinotrimethylenehydrazinocarbonyl, aminodimethyleneamide carbonyl, bromocarbonyl, phenylenediazonicum, inthiocyanate, These are semicarbazide and thiosemicarbazide groups.

For clarity, some selected R1-substituents are listed below: -CH2-C,! (, -0(CH2)5Co2CH,C
,H5,-CH2-C,H4-0-CH2-Co2CH
2C, H5, -CH2-C, Hdi0(CH2)5Co anti-HNH2, -CH2-CqH4-CONHFJHノ\/
, -CH2-C,5H,-0(42)4-8Hs-
CH2-C6H4-0(CH2)3NHNH2, Li-CH2-C,H,-0(CH2), C0NHNH-(
CH2) n-doHNE(2, -CH2-NHNH2, -
CH2-3H, -CH2CONHNH2, -(CH2)
3SH, -CH2-C6H4-0-CH2COBr.

-C,5H4NHCOCH2Br, -CH2-C,
5H4-OCH2-C-NH-(CH2)2NH2, -
CH2-C6J-NH2, -C6H4-N2, -C6H
4NHC8.

-NHCO-NH-NH2, -NHO2-NH-NH2
, -CH2-C,H4-0-OH2-C-NH-(CH
2) 10-C-NHNH2, l -CH2-C,H, -0-CH2-CHOH-CH2-
NH(CH2),. -C-enclosure 2, -0CH2-C-N
-CH2-(C'HOH)4-CH20H1-CH2-
0-(CH2)4-8H, -CH2-0-(CH2)3
-NHNH2, -CH2-0-CH2-C-NH-NH
2, -CH2-O-CH2-CH2-NH2, in all cases where the azide water t2+ is not stirred by the central ion, one, several or all residual hydrogen atoms are inorganic and/or Physiologically tolerable cations of organic bases or amino acids can be substituted if desired. Powerful inorganic cations are, for example, lithium ions, potassium ions, calcium ions and even sodium ions. Organic base Q-tolerant cations are especially those of primary, secondary or tertiary amines, such as ethanolamine, jetanolamine, morpholine, glucamine, N,N-dimethylglucamine and especially N-methylglucamine. .

Permanent cations of amino acids may be, for example, lysine, acetic acid (in which case it is the blue hormone, dext 2), polysaccharides, polychelone, etc.
), and droxyethyl starch, polyethylene glycol,
Desferrioxasamine (Desferrioxas)
ine), pleomycin, insulin, prostaglandin, steroid hormone, amino glue, amino acid,
Peptides such as polylysine, proteins (eg immunoglobulins and monoclonal antibodies) or lipids (also in the form of liposomes). Albumin, e.g. human blood γ
albumin, antibodies, such as monoclonal antibodies that bind to tumors and are % specific to the fc antigen, or antimyosin (
complex with Anzimyosin (Konj uga
te) can be particularly emphasized. Instead of biomolecules, commonly available synthetic polymers, such as polyethyleneimine, can also be attached. The diagnostic agents produced therefrom are suitable, for example, for use in prosthesis and infarction diagnostic methods. Monoclonal antibodies for conjugation are particularly applicable to those that are directed against antigens mainly located at the cell membrane. Such substances include, for example, monoclonal antibodies or fragments thereof (F(ab)2) for tumorigenesis. -hCG) or other antigens such as glycoproteins. Also of particular interest are anti-myosin, anti-insulin and anti-fibrin antibodies.

The conjugation or clathrate compound with liposomes is suitable for hepatic FA intake or for cancer diagnostic methods (for example, it can be used as mono- or foam-like phosphatidylcholine-cholesterol-vesicles). It will be done.

Complex formation takes place via the carboxyl group of the complexing acid or via the functional groups, as described in detail above, present at the end of the C1-C2o-alkylene group of substituent R9. When forming a complex between a complexing acid and a macromolecule, several acid residues can be combined with it. In this case each complexing acid residue can have a central ion.

Desired macromolecules can be produced by methods known per se) For example, Rev, roum, Morphol, Emb.
ryol.

Physiol, , PhysioLogie i9
1881, vol. 18, p. 241 and J. Phanm, S.
ci, Vol. 68, 79 (1979), the activity of the complexing agent with the nucleophilic group of the large Fili molecule, such as an amino-, phenol-, sulfhydryl-, aldehyde-, or imidazole-group. The same effect can be achieved by reaction with derivatives. Examples of activated derivatives include -
Monoanhydride, acid chloride,
Acid hydrazides, mixed anhydrides (e.g. G, E, Krej
Carek and L. Tucker, Bioc
hem, Biophys, Res, Commun
, i 977, 581), activated esters, nitrenes or inthiocyanates. Conversely, it is also possible to react activated macromolecules with complexing acids. For complexing with proteins, e.g. C, H, N2,
C,H4NHCOCH2, C,H4NHC3 or C6H
40CH2CO structure f! L substituents are also used.

The inventive formation IC/) conversion compound can be prepared in a manner known per se from formation II: H2N-CH-CH-N-CH-CH-NH2(U) [
In the formula, R2 and R3 represent a (CH2)- group, m represents 0 or 1, and in this case R41 and R51
simultaneously represent a hydrogen atom, and in R4', R8/
represents a hydrogen atom or R91, where R91 optionally has a p-imino, phenyleneoxy, phenyleneimino, amide-ester group, oxygen, one sulfur and/or one nitrogen atom, and optionally A group that can be substituted with a hydroxy, mercapto, imino and/or amino group and converted into a functional group containing straight chain, branched chain, saturated or unsaturated R9? [representing a C--C2°-alkylene group having a terminal] amine with a) phosphorous acid/formaldehyde or b) the compound HalCH2COOR1° [in the formula, Hal is a chlorine atom,
a bromine atom or an iodine atom, and HILI represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms]
alkylation in the presence of a base using acetic acid, followed by removal of the optionally present alkyl group R10 by acupuncture and, if desired, the acetic acid compound thus obtained.
Compound 1.1v or V: [In the formula, RII represents a hydrogen atom or a CH2C00H- group, Bll represents a c1%c,-alkyl group, A and Z together represent a scattering atom, or A is a hydroxy group and 2 represents a group 0R11] with an amine of the form vI:, optionally still present ester IIs is converted, or - a bisanhydride of the form 1a is reacted with an alcohol R120H. , the acid of the general formula I [in which Y represents a hydrogen atom] obtained in this way is, if desired, a) prepared by a method known per se, with an atomic number of 21 to 29.31.3.
2.38.69.42-44.49 or 57-70 or at least 11 metal salts of elements 57-70 or 77 are reacted and polished, if desired, the azide hydrogen atoms present are removed. by substitution with inorganic and/or organic bases or cations of amino acids, or b) in a manner known per se, with atomic numbers 21-29.61, 3
2, 38, 69.42-44.49.57-70 or 7
Gold S reacted with at least one metal oxide or metal salt of 7 elements and subsequently treated! lf#- is bonded to the macromolecule in a manner known per se via the functional group contained in R9' or by the CO- group contained in V2 and, if desired, the azide hydrogen atoms present are bonded to the inorganic and /
or substituted with an organic base or an ion-resistant amino acid,
or c) by a method known per se, to the macromolecule via the functional group contained in R9' or by the CO-5 contained in v2, and subsequently by a method known per se, atomic number 21 ~
29.61.32.38.39.42-44.49.5
7 to 70 or 77 elements, and then reacting with at least one gold pA oxide or metal salt of the elements 7 to 70 or 77, and subsequently forming the desired pIT.
The conversion is carried out by replacing the azide hydrogen atoms present with inorganic and/or organic bases or amino acid ions.

p-substituted 6,4-diamino-12,5-bis-(aminemethyl)-pyrrolidine-13,5-diamino- and 2,6-bis(amino Methyl)-piperidine is an amine of the form II: in which B2, H3, R4' and R51 are as defined above. This is known in the literature (J.

Pharm, Sci, Vol. 58, p. 1038 (1969
) or in a manner known per se, for example using Roseumn charcoal or Nijimura as a catalyst.
Catalysts (Houben-Weyl, Methoden
der organischenChemie, vol. 4/1c, p. 256, GeOrg Thieme-Ver
lag, Stuttgart, New York
l 98Q, F.

Zymalkowski, Katalytische
Hydrierung.

Ferdinand Enke-Vertag Stu
ttgart 1965) using catalytic water*'et
from the corresponding aromatic precursor (Roe, d
o Travaee de Chim, desPay
s-Eas 72569 (1953), Ann,
Ch em.

537 (1978), J-Pharm, 80C1J
APAN Volume 79, 549 (1959) Served.

Amines each bearing the desired R''-1f group are conventionally substituted in a similar manner to the next educt (e.g. keridan (
41 (Chelidansa'ure) and then converting the radicals directly into the literature by methods known from the literature (for example alkylation with brombenzyl conductors).

A substituent p91 that can be converted into an ey+ group R9 having a functional group suitable for bonding to a macromolecule at the terminal
Particularly suitable are hydroxy- and nitrobenzyl-, hydroxy- and carboxyalkyl- and thioalkyl groups (having up to 10 carbon atoms).

This can be prepared by a person skilled in the art using methods described in known literature (Chem,
Pharm.

Bull, 33674 (1985), Compe.
ndium ofOrg, 5ynthesis i
-5 volumes, Wiley ancl 5onS engineering nc,)p
fr desired ft group (if kept, the official H group is amino-, hydrazino-, hydrazinocarbonyl-, methacryloylhydrazinocarbonyl-, maleimidamide carbonyl-
, halodeno, halogenocarbonyl, mercapto group), in the case of a nitrobenzyl group,
First, catalytic hydrogenation (e.g. P, N, Rylande
r, Catalytic Hydrogenation
over Platinum Metals Aca
demicPres81967) must be carried out to make 54 aminobenzyl bodies.

Examples for the conversion of hydroxy or amino groups are acid acceptors such as sodium hydroxide, sodium hydride or alkali metal or alkaline earth metals in anhydrous neutral solvents such as tetrahydrofuran, dimethoxyethane or dimethyl sulfoxide. In the presence of carbonates, such as sodium carbonate, magnesium carbonate, potassium carbonate, calcium carbonate, it is carried out at temperatures between 0° C. and the respective L:D boiling point I7), but preferably between 20° C. and 60° C. General 2~11: w-L-Fu (Vll) [wherein W is a +'i 1jt substituent (Nucloofu, gJ e.g. Ha
t, Br, engineering, CH3C1gH, 803, or cp',
so, fractional representation, L represents an aliphatic, aromatic, arylaliphatic, branched, straight chain or cyclic hydrocarbon group having 20 to 7 carbon atoms, and Fu represents a functional group at the desired terminal position. [expressed] with a substrate.

- Examples of compounds of the form vn include: Er(CH2)2NH2, Br(CH2)'30H,
BrCH2COOCH3, BrCH2C02Bu XB
r(CH2)4C02C'2H5, BrCH2C0Br
.

BrCH2CONH2, CICH2COOC2H5, B
rCH2C0NHNH,, BrCH2CH-CH2゜carboxy group can be converted using, for example, the carbazimide method (
Fieser, Reagents for Or,
ganicSyntheses 10142) mixed anhydride (Org, Prep, Proc, In
t, 7215 (1975)) or activated engineering, chill (Adv, Org, Chem.

Part B % 472).

For the synthesis of compounds containing phosphorous acetic acid residues of formula I according to the invention, methods known to those skilled in the art in the amine industry of formula H (Phosphorous and Sulfur 19
83.16233) and react with cyformaldehyde/phosphorous acid.

- an amine of the form H with the formula: HalCH2COOR" [wherein Hal represents a chlorine atom, a bromine atom, or an iodine atom, and p10 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms] Depending on the choice of Jfi auxiliary base, the corresponding tetracarboxylic acid (Rla -
a) or its ester or the corresponding pentacarboxylic acid <R1'===CH2"○OH) or its ester is obtained.

Suitable auxiliary bases are all bases known to the person skilled in the art for alkylation reactions, such as alkaline and alkaline earth metal carbonates, alkali and alkaline earth metal hydrogen carbonates,
Polymer gap ion exchanger and commonly used organic auxiliary bases,
For example, triethylamine, tetramethylpiperidine, pentamethylpiperidine, proton sponge (Pr0tO
nensCbvrann) and tetramethylguanidine. For the production of tetraacetic acid compound, lithium carbonate, sodium carbonate and amberlite (
Amberlit, e) LA2"' is preferred; potassium carbonate, tetra- and pentamethylpiperidine are preferred for the preparation of compounds containing pentaacetic acid residues.

As bath agents all solvents which can be used for the alkylation are preferably used, preferably tetrahydrofuran, dimethylformamide,
Dimethylacetamide and dimethylsulfoxide are suitable.

Tetra-acid-substituted complexing agents (general formula 1 in which R1 and Y represent hydrogen atoms) can be obtained by catalytic hydrogenation of the corresponding aromatic tetracarboxylic acid or its ester by the method described above (Chem. , Berichte 13
7, 948 (1984).Subsequent -alkylation in a manner known per se provides the desired interacetic acid α-substituted various compounds rIJ.

The necessary saponification of the acetate groups that may be formed is
It is carried out by methods known to those skilled in the art, for example using basic catalysts, such as alkali or alkaline earth metal carbonates or hydroxides.

General formula I [wherein yl and/or v2 B coNp6R
4 of the rounded amide group for the production of compounds of '-representing a group]
One carries out this by partially converting the carboxyl groups of the aminotetra- and aminopentacarboxylic acids obtained in the above-described process into amide- or mono- or polyhydroxyalkylamido-groups. In this ninth step, all synthetic possibilities known to the person skilled in the art are taken into account. One example for this is the general formula 1-V:
and 2 together represent an acidic atom or hydroxy group t-, and 2 represents a group: □BL1] and an anhydride or ester of the general formula v1: [where R6 and R7 are ] with an amine.

Suitable amines include, for example, dimethylamine, diethylamine, s-n-propylamine, diisopropylamine, di-n-butylamine, diisobutylamine, s-s-butylamine, N-methyl-
n-i.

Bylamine, dioctylamine, dicyclohexylamine, N-ethylcyclohexylamine, diisozolobenylamine, benzylamine, aniline, 4-methoxyaniline, 4-dimethylaminoaniline, 6.5-dimethoxyaniline, morpholine, pyrrolidine, piperidine,
anti-methyl-piperazine, N-ethyl-piperazino, N
-(2-Hydroxyethyl)-piperazino~N-(hydroxymethyl)-piperazine, piperazinoacetic acid isopropylamide, N-(piperazinomethylcarbonyl)-morpholine, N-(piperazinomethylcarbonyl)-pyrrolidine, 2- (2-hydroxymethyl)-1-piperidine, 4-(2-hydroxyethyl)-piperidine, 2-
Hydroxymethylpiperidine, 4-hydroxymethylpiperidine, 2-hydroxymethyl-pyrrolidine, 6-hydroxybiperidine, 4-hydroxy-piperidine,
3-Hydroxy-pyrrolidine, 4-piperidone, 6-viroline, 1-piperidine-6-carboxylic acid amide, piperidine-4-carboxylic acid amide, piperidine-6-carboxylic acid dienalamide, piperidine-4-carboxylic acid dimethylamide, 2 , 6-dimethylpiperidine, 2.6-
Dimethylmorpholine, N-7 cetyl biperazone, '-
(2-hydroxy-propionyl)-piperazine, N-
(3-hydroxy-propionyl)-piperazino, N-
(methoxyacetylcupiperazine, 4-(N-acetyl, N-methylamine)-piperidine, piperidine-4
-Carboxylic acid-(6-oxapentamethylene)-amide, piperidine-3-carboxylic acid-(6-oxapentamethylene)-amide, N-(N',N'-dimethyl-carbamoyl)-piperazine, pyrazoline, pyrazolidine ,
imidacilline, oxazolidine, thiazolidine, 2,3
-dihydroxypropylamine, N-methyl-2,6-
Dihydroxypropylamine, 2-hydroxy-1-(
hydroxymethyl)-ethylamine, N,N-bis(2
-Hydroxyethyl)-amine, N-methy#-2,3゜4.5.6-pentahydroxyheyacylamine, 6-7
Minnow 2,2-dimethyl-1,3-shiokisekan-5-
ol, 2-hydroxyethylamine, 2-amino-1
, 3-propanediol, jetanolamine, ethanolamine.

The polyhydroxyalkylamines can also advantageously be used in reaction-protected form, for example as O-acyl derivatives or as ketals. This is especially true if this derivative can be produced more easily and cheaply than the polyhydroxyalkylamine itself. A typical example is 2-amino-1-(2,2-dimethyl-1°6-
thioxolan-4-yl)-ethanol, 1-amino-
Acetonide of sibutane in 2,3,4-trihydro (West German Prisoner's License Publication (DE-O8) No. 3150917
(Manufactured according to No. MB).

Subsequent removal of the protecting group can be carried out quickly, for example by treatment with a dispersive ion exchanger in an aqueous-ethanolic FW solution.

For example, US Pat.
No. 8 Specification Coordination or West German National Policy Publication (DE-o)
s) It can be carried out using acetic anhydride r in dipyridine according to the method described in No. 81695050 aAa.

However, in certain cases it may be particularly advantageous to carry out the water removal carefully with a carbodiimide in a suitable layering agent, for example dimethylformamide or dimethylacetamide.

The preparation of monoanhydrides of formula 1v can be achieved, for example, by J, A, O, C.

8.59 (2) 105 (1982), C, A.

96 Vol. 164556u (1982)) and bis-anhydride V) partial hydrolysis.

- The preparation of monoanhydrides of type V is an example of diethylenetriaminepentaacetic acid-ethyl ester monoanhydride, D
TPA monoecarnister (J.

Starting from Pharrn, Sci, (SF 3, 1979 194 negative), diN'-(2,6-dioxomorpholinoethyl) + N6 should be described.
- (Ethoxycarbonylmethyl)-3,6 acetic anhydride 2
N3 in 50m1. N6-bix-(carboxymethyl J -wQ-(ethoxycarbonylmethyk)-3,6,
9-triadeundecanedioic acid 21.1, p (s o
After addition of 42.211 u of pyridine, the suspension of 1 mmol) is stirred at room temperature for 3 days. Then Shen I! i is filtered with suction, washed in each case 6 times with anhydrous vinegar rR50M, and it is subsequently stirred for several hours with anhydrous diethyl ether. After filtration with suction, washing with anhydrous diethyl ether and drying in vacuo at 4000 °C, 18.0 g (=8!89% of theory) of a white powder with a melting point of 195-196°C are obtained.

Analysis (for anhydrous substance) C47,64H6,25N10.42 (calculated value) C47
, 54H6, 60N10.22 (actual image) The conversion of this acid anhydride into an amide according to the invention is carried out in the liquid phase.

The noisy reaction medium is water, for example, double 1F! Injection agents such as acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethylacetamide and the like or mixtures thereof. The reaction temperature is approximately 0°C to 1
Temperatures of between 20°C and 80°C are advantageous in this case. The reaction time was between 0.5 hours and 2 days;
Especially the 1 hour and 66 hour periods.

The esters of general formulas 1 and IY can be prepared by known methods, for example, as described in J. Pha by R.A. Guilmette Temple.
rm.

Sci, Vol. 68, 194 Negative (1979), and 1v
is rice 7% 7f ((US-Patent)! 3497
It is stated in the Particulars of Oath No. 535 and is enforced according to the second son law.

Amitrilysis of the esters is carried out in the liquid phase, for example at the 4-degree high point, in one agent, for example dimethylformamide, dimethylacetamide or dimethylsulfoxide. The reaction temperature is about 20°C to 2000C, in this case 1
Temperatures from 00'C to 180'C are common. Reaction time is 2 hours and 2 days in the dark, in this case 4 hours to 56
The reaction time of hours is significant.

The number of ester groups for the production of compounds of general formula I [in which V1 and/or V2ζC00R12- groups] is as follows:
This is carried out by methods known in the literature, for example by reaction of a bisanhydride of the form Ia: with an alcohol of the general formula R120H.

Furthermore, all methods known to the confectioners for converting carboxyl groups into amide groups, such as Krej via mixed anhydrides, can be used.
Biochem, by Carsk and Tucker.

Biophys, Res, Connmun, 77
The method according to Vol. 581 (April 1977) may be cited for the synthesis of the general formula 1 (D &it series) according to the invention.

Manufacture of gold-end fibula according to the invention]
) No. 71564, European Patent Organization (EP) No. 13
Specification No. 0934 and West German State Office Publication (DE-
O8) No. 3401052 Meiji aJ, atomic number 21-29.31.32.38.
39.42-44.49.57-70 or 77 metal oxides or metal salts (e.g. nitrates, acetates, carbonates, chlorides or sulfates) in water and/or lower alcohols (
e.g. methanol, ethanol or μ-isopropanol)
A complex-forming acid θ of the general formula I in which Y represents a hydrogen atom in water and/or a lower alcohol
This is done by mixing the liquid or suspension and, if necessary, warming it or heating it to the boiling point and stirring until the ash is finished. If the resulting complex salt is incompatible with the solvent used, it is isolated by separation. In the case of soluble bath liquids, for example by spray drying? It can be isolated by evaporation to dryness.

There are still acid groups present in the resulting complex salt.

In this case, it is often possible to change the enemy complex salt to a neutral fin salt with an inorganic and/or organic base or amino acid that produces physiologically acceptable ions, and reduce the total height of sword and Tsuko γL4. Nari de Ruru. In many C/) 43 cases μ this is unavoidable,
This is because by transferring the 1-salt thickness (8d is -) to VC for 1 year, it becomes possible to isolate or at least purify a single product for the first time. This is because it is suppressed.

In this case, the oxidation is for example an alkalinity of sodium, potassium or lithium! bases (e.g. hydroxides, carbonates or mineral carbonates) and/or organic bases such as especially p-18- and t-amines, e.g. ethanolamine, morpholine,
Glucamine, -methyl- and N,N-dimethylglucamine, strictly basic amino acids such as lysine, l-luyanine and ornithine are used.

For the preparation of neutral complex compounds, it is possible, for example, to add to the acidic complex salt in aqueous solution or suspension an amount of the desired base in l to achieve the neutral point. Mix the generated neutral salt with water
Addition of a J-functional z4 agent, such as lower alcohols (methanol, ethanol, isonoropanol, etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) to precipitate Vζ. It is often advantageous to prepare crystals that can be easily isolated and purified in this way. It has proven particularly advantageous to add the desired base during the bulk formation of the reaction mixture and thereby save process steps.

It is often advantageous to form acidic complexes with several free azide groups.

This can be done, for example, by reacting a complex-forming acid in an aqueous suspension or solution with an oxide of the element that provides the central ion and with half the amount of organic base glue necessary for neutralization, and the resulting complex salt being monofunctionally , rgT, if desired, and then by mixing with an inorganic base for complete neutralization. The order of base addition can also be reversed.

In the case of convenient use of pheasantized proboscis containing radioactive isotopes,
Its manufacture is 'Ra(lift, racers f'o)
rMedical Applications' Volume 1 CRC-Press, Boca Radon, Flo
It is written in the Rida and can be carried out according to the second son law.

The production of the diagnostic agent according to the invention can likewise be carried out in a manner known per se, by suspending or dissolving the complex compound according to the invention in an aqueous vehicle, optionally with the addition of additives customary for galenic preparations.
This is then carried out by pouring the suspension or bath solution into a container. - A suitable additive is, for example, a physiologically tolerable @biliquid (e.g. trometham).
in) complexing agents (e.g. diethylenetriamine-interacetic acid); in small additions or, if necessary, electrolytes such as sodium chloride or, if necessary, antioxidants, e.g. ascorbic acid.

If a suspension of the drug according to the invention in water or physiological saline rH solution is desired for enteral administration or for other purposes, it may be added to 1r1 or several Galethus 1#. Adjuvants commonly used in punishment (e.g. methylcellulose, lactose, mannitol) and/or intercalary agents (e.g. lecithin, Tween)
s (R), Myrj (R)) and/or #: are mixed with a taste-masking 1ζ aromatic substance (for example, nitrous oil).

In principle, the diagnostic agent according to the invention f! : It can also be produced without isolation of the complex salt. In each case, special care must be taken that the chelation is carried out to such an extent that the salts and salt solutions according to the invention practically do not contain non-chlorinating electrical metal ions. This can be ensured, for example, by control titration during the manufacturing process using a color indicator such as xylenol orange. The invention therefore also relates to the preparation of complex compounds and their salts. As a last safety measure, the isolated 1-salt ↑# product remains.

of the complex compound in water or saline bath solution for oral administration or other c/) purposes! If the solution is desired, a slightly soluble complex compound t14 or 1. The galenic preparations of J are mixed with customary auxiliaries and/or surfactants and/or aromatic substances for taste correction.

The diagnostic agent according to the invention contains 1 mol of the complex salt, in particular 1 μmol to 1 mol, and is generally administered at a dose of 0.001 to 5 mmol/kg. This is determined by rounding & intraluminal and parenteral administration.

The fine compounds according to the invention are suitable for: 1) MMR-, Rentke-9-1 and ultrasound-diagnostic methods in the form of their complexes with ions of elements with atomic numbers 21-29.42.44 and 57-70; 2) Atomic number 27.29.31.32.38.39.4
It is used for radiodiagnosis and radiotherapy in the form of its complexes with radioactive isotopes of elements with 3.49.64.70 and 77.

The drug β according to the invention fulfills various requirements for suitability as a contrast agent for nuclear spin f@layer imaging. In other words, this can be done by increasing the signal strength by oral or extra-oral administration! I am extremely interested in improving the images that can be served with shadows with its proof power. Furthermore, this is
It shows a high efficacy, which is necessary to load the body with as little foreign material as possible, and a good tolerability, which is necessary to preserve the non-invasive axis of the vI4 hill (J.

Compute, Tomography 5, 6:
546-46 (1981), Radiolog 71
Volume 44, page 643 (1982) and Brevet 5
special daMedicament Nr, 4
84 M (1960) (for example, the compounds listed in 84 M (1960) are too toxic and tb), it is possible to prepare solutions of Xs degree with good water bathing properties of the drug according to the invention, thus making it possible to replace the volume load of the circulation. can be maintained within a range and can equilibrate the dilution with body fluids. Furthermore, the agents according to the invention not only exhibit high stability in vitro, but also exhibit high stability in vivo, thus preventing the release or exchange of non-covalently bound ions in the complex, which are themselves silane. The new (/J) procedure is carried out very gradually within the time period for complete excretion of the contrast medium. For example, 1% RI with proteins and antibodies used for diagnosis - already at low cost. N unusually high signal analogy f!: Since it causes this martyrdom, it is correspondingly low?
Six liquids of trowel strength can be used.

The medicament according to the invention is generally used as an MR-diagnosis agent at a dosage of from 0 to 5 mmol/kg, in particular from 0 to 5 mmol/kg.
．． Administer at 0.005-0.5 mmol/Yunobon. For example, H, J., Weinmann et al., A.
M, J, of Roentgenology 14
Discussed in Vol. 2, p. 619 (1984).

NMR, which uses a paramagnetic contrast agent, as opposed to the conventional Rentoden diagnostic method, which uses a radiopaque contrast agent.
- In the diagnostic method used, no linear dependence of signal enhancement on 71i1 degree occurs.As shown by the 0 control test, increasing the applied dose does not result in signal enhancement in the absence of paramagnetic; If the contrast agent is used sparingly, the signal may disappear. For this reason, it was surprising that some pathological processes of di-paramagnetism became visible only after administration of a much higher shadow field according to the invention. In other words, an example is a head tumor (Cra:
11alen Abzesses) defective blood-brain barrier (Blnt-Hlrn-8chranke) V
) Verification is performed using paramagnetic complex salts, such as Gad IJ Ni-2,
6-bis-(N,N-bis(carboxymethyl-no-aminomethyl)-1-piperidino-fraudic acid and 0.05 to 2.5 mm' in the form of a well-washed salt)/kg, especially 0
．． It is only confirmed after administration of 1 to 0.5 mmol/9. 0.1 mmol/Yuyoshi is also a large dose! for,
1 mole/! Higher field strength up to 0.25°, especially 0.25-0.
A solution of 75 mol/-13 is necessary, since only then can the volume load be reduced and the handling of the injection solution easily ensured.

Particularly low doses of organ sex NMR-diagnostic agents (1 to 9
(below) can be used, for example, to detect seed parts and myocardial fecal base. Furthermore, the complex compounds according to the invention can be used advantageously as displacement reagents. The drug according to the present invention is suitable as a contrast agent for iodine-containing contrast agents in VA and biochemistry. ill VC
It is emphasized that the better known anawalaxy-like reaction L/) symptoms are not observed here. This is Tejip
h + traction method (digitaLe 5ub-t
Due to the advantageous absorption t+ in the higher brightness and voltage range for RAKTINIC STECHNIK), N is required for the load.

RakuMIJri, by virtue of the invention, is generally used for use as a contrast agent for meglumine-diadolic agents.
(Meglumin-Diatrizo)
at) 0.1 to 5 mmol/kg,
In particular, doses of 0.25 to 1 mmol/kg of violet are administered. For details on the use of Lentoden contrast agents, see e.g. 11i Barke.
Author, Rontgenkont-rastrnittel
, SkinThieme, Leipzig 1970 and P., Thurn, E., Bucheler”E.
infMhrung 1ndie Rontgendi
agnostik' C), Thieme, St.
Discussed in Uttgart New York 1977.

The medicament according to the invention (because its acoustic impedance is higher than that of body fluids and tissues) is also suitable as a contrast field for ultrasonic diagnosis, especially in the form of a suspension. This is-
Generally it is administered at 0.1 to 5 mmol/kg, especially from 0.25 to 1 mmol/kg.

For details on the application of ultrasonic diagnostic agents, see T and B, for example.

Tyler et al., Ultrasonlc Imagine
g 3.323 (1981), J, 1. Haft
'J,' C1inicC11nicalEchok
ardio” Futura, Mt.
K15co New York 1978 and G,
5tefap%F,'Echokar-dlogr
aphie' G, Thieme Stu
llgart/New York 1981.

The drug according to the invention is also popular as a radiodiagnostic agent due to its advantageous radioactive properties and the good stability of the complex compounds contained therein.

V) For details on usage and dosage, please refer to Ir! ' Rad
io-tracers for Medical
Applications ”CRCPre
ss, Boca Raton, Flonida K
Are listed.

The invention is illustrated in detail with reference to the following examples.

Example 1 2.6-bis[N,N-bis(carboxymethyl)aminomethyl-1-piperidine-rrF, acid 2.6-bis(N,N-bis(ethoxycarbonylmethyl)aminomethyl-1-piperidine-acetic acid) Ethyl ester 31.69
(55.0 molar dioxane is poured into 1609 liters of dioxane, and this u solution is diluted with 160 liters of water. To this bath solution, 30.6 d of 11N caustic soda is added while stirring and slowly heating to 80°C. Hold at 80℃ for 1.5 hours,
After cooling at 0°C, adjust the pH to 2 with S-hydrochloric acid. Add this acid solution to a cation exchanger of Amberlite IR120 type, rinse the exchanger with sufficient water, and then double the concentration. Wash off with ammonia bath. The crude product obtained by evaporating and concentrating this eluent was dissolved again in 400 ml of water and adjusted to 26 ml by adding 120 ml of water. The exchanger is filtered with suction and the aqueous solution is concentrated by evaporation.

The residue (18.1g) was mixed with 17Qml of mepnoh and 1Q of water.
The kidneys are heated in a rnl solution and gradually cooled.

Colorless crystals with melting point 189-191°C 13.8. ! V(F
! 57 points of the theory of theory) are removed.

Analysis: Calculated value: C47, 11H6, 28N9.70 Measured value: C
47,LJ2 H6,30N9.64 The starting price is transferred in the following manner: a) 2,6-bis(aminomethyl)piperidine 2.6
-Bis(aminomethyl)pyridine 6-barrR (Anna
len der Chemie 137-544 (19
78) ) 123.3 g (0.5 mol) of water 2.5
Hydrogenate in an autoclave at a maximum of 50° C. and an initial pressure of 16 bar for one hour with the addition of 25 g of rhodium/charcoal as a catalyst. The repellent is filtered off and the colorless filtrate is reduced to dryness in vacuo. The oily residue is dissolved under heating in 125M methanol and then concentrated again by evaporation. The obtained foam is 1□□□ order V
C First, 600 ml of methanol, then 600 ml of acetonitrile.
Stir in 00M at 25°C, filter and dry in X9. A colorless, highly hygroscopic powder with a melting point of 263-264"C is used.

Analysis: nX value: C33,28H7,98N16.64 C”
,j! 42.111 measurement value: C33,31H7,91N
16.50c1!42.13b) 2,6-bis(N,N
-bis[ethoxycarbonylmethyl]aminomethyl]-
1-Biperidine acetic acid ethyl ester 2,6-bis(aminomethyl)piperidine 6 salt GL!
50,521I (200m%) was added with stirring in 1200ml of dimethylacetamide with 165ml of potassium carbonate.
Add 8 g. Bromoacetic acid ethyl ester 1<57M
(1.5 mol) is heated to 100° C. for 24 hours. After cooling to 25° C., the filtrate is concentrated in vacuo. A replenishing oil is obtained as a residue, which is poured into 1200 m of acetic ester. 300% organic phase of sphagnum moss
Washed 4 times with 1-1, dried over sodium imtate, d+! filtrate and condense the filtrate in vacuo. A crude product was obtained, which was subjected to column chromatography (silica gel) to obtain 4=[methylene chloride/methanol (as agent)].
95:5). A clear oil 78y (68y theoretical) is obtained, the purity of which is determined by chromatography.

Analysis: Calculated value: C56, 55H8, 26N7.32 mountains (j constant 1
Direct: C56,44H8,12N7.39 example 2 2.6-bis[:N,N-bis-(carboxymethyl)
Aminomethyl-2-piperidine 2.6-bis(N,N-bis-(ethoxycarbonylmethyl)-aminomethyl-1-piperidine/hydrobromide 28.4 g (50 z mol)) in dioxane/water (1:1)
Dissolve in 200mA.

Add 27% of 11N caustic soda while stirring and heating to 80°C.
punishment? Add drops, G liquid? Hold at 80°C for 1.5 hours. After cooling to room temperature, acidify to PI''12 with hydrochloric acid and charge the acidic liquid onto a cation exchanger of type Amberlite Eva 120. Wash the exchanger with sufficient water and then dilute it twice. M is separated with Monia.A crude product is obtained by evaporation shrinkage of the M solution, so this is treated with V(d) in 300a of water.Subsequently, this bath solution is adjusted to Pb0.0 with IF1120.This exchange The body was aspirated and the heart fluid was condensed with a PC nitrate.The residue was reconcentrated from methanol/X (10:1) to form colorless crystals with an odor point of 129-132°C.
3.5, F (72% of total yield) is obtained.

Analysis: 'tt'x value: C48,00H6,71N11.9 Measurement: C47,78H6,97N11.02 The material from the mountain is collected at the manufacturing site in the following manner: a) 2.6-bis(N,N- Bis(ethoxycarbonylmethyl)aminemethyl]-piperi2.6-bis(aminomethyl)1-piperidine trihydrochloric acid (prepared in Example 1a) 25
．． 29 (100 mmol) in dimethylacetamide 600
From acetic acid ethyl ester suspended in 61.ml.
17M (550 mmol) and 410 ml of the liquid anion exchanger Amberlite LA2 (C900m"4M) are added.

After heating to 60° C. for 24 hours + WJ and cooling at 25° C., the common agents were removed by suction, and the oily residue was stirred with 2 ml of n-pentane and Vc. A colorless precipitate was obtained, which was washed several times with n-pentane after filtration and then incubated at 40° in Makabe.
Dry at C. A sword that yields 38.9 g of raw matting.
Then, this portion was recrystallized from 400M acetate. 61 g of colorless crystals with a melting point of 116-117°C (55% of the theoretical amount)
) is obtained.

Analysis: Calculated value: C48,49H7,45N 7-39 B
r 14.06 example foot value: C48,80H7,51N
The desired tetraester (hydrobromic acid) of 7.20 Br 13.81 Ffr is prepared in a similar manner using lithium carbonate and sodium carbonate as auxiliary bases.

Example 3 2.6-bis[N-carboxymethyl-N-(2,3-
Dihydroxy-N-methylglobin (rubamoylmethyl)-aminomethyl>1-piperidineacetic acid 2,6-bis(2,6-dioxomorpholino-methyl)
-1-piperidine acetic acid 4.0. ′? (10 mmol) (commonly understood as anhydrous N-methylpyrrolidone CP)
Methylaminopropane-2,3-diol 2.1 j9
(20111 mol) is added. The bath liquid is warmed to 60° C. for 5 hours and then stirred at room temperature for 16 hours, and the bath agent is removed in vacuo. The residue is stirred in diethyl ether 100M.

A colorless precipitate is obtained which is filtered and dried in vacuo. 4.6 g white powder with melting point 104-108°C
(76th of the burial ceremony) is prayed.

Analysis: #f Calculated value C49,42N7.47 N11.53 Measured value C49,27N7.19 N11. (57 starting W7 prizes are manufactured by the following method.

a) 2,6-bisC2,6-dioxomorpholino-methyl)-1-piperidineacetic acid 2,6-bis[N,N-bis(carboxymethyl)aminemethyl]-1-piperidineacetic acid (prepared in Example 1) )4.3
．． 9 (10 mmol) in 80 rnl of dimethylformamide
Dissolve under heating with dp K and cool the solution to 5"C. Dicyclohexylcarbosiimide (solid) 4
．． 2 il (20 mmol) are added under stirring and cooling. The dicyclohexylurea formed during cooling for 12 hours is expelled as a white bulky precipitate. This is filtered and the fg is truncated in vacuo at a maximum of 50°C. A clear yellow oil is obtained from which the desired anhydride can be precipitated by stirring with various organic solvents, preferably with an organic ether such as diethyl ether. White 1! !
, a powder bed is obtained which is hydrolyzed on exposure to air. Therefore, the desired anhydride was confirmed in the IR-spectrum in a dimethylformamide bath with an anhydride absorption band of 182.
0 and 1780 (m″″l cooa 1640 cI
n-1), the f# liquid is concentrated in vacuo and the residue is taken up in the desired bath agent, preferably N-methyl-2-pyrrolidone, for reaction with the hydroxyalkylamine.

Example 4 2.6-bis(X-carboxymethyl-[bis(2
-hydroxyethyl)-rupamoylmethyl]-aminomethyl)-1-piperidineacetic acid 2,6-bis(2,6-dioquinmorpholinomethyl)-
1-Piperidineacetic acid (prepared in Example 6a) 9.9! '(
25 mmol) (#i!i water dimethylform 7mide 150
Jetanolamine 5.251 (5
0 mmol) was added, and the m solution was heated to 50° C. at 5:00 IMI. After stirring for 16 hours at room temperature, the solvent is removed in vacuo.

The residue is stirred with 150 ml of diisoglobyl ether, resulting in a colorless precipitate. a. After filtration and drying in vacuum, a colorless powder with a melting point of 141-146°C12.
21% of the theoretical value) is obtained.

Analysis: Calculated value C49,42N7.46 N11.53 Measured value C49,70N7.32 N11.41 When used in a similar manner with ethylamine, 2,6-bis-iN-carboxymethyl-N-bis(ethyl)°-carbamoylmethyl ]-aminomethyl)-1-piperidineacetic acid is obtained, and with morpholine, 2,6-bisitJ-carboxymethyl-N-[bis(morpholinyl]-carbamoylmethyl]-aminomethylJ-1-piperidineacetic acid is obtained.

Example 5 2.6-bis[M-carzoxymethyl-N-(2,3,
4-trihydroxybutylcarbamoylmethyl]-7minomethyl]-1-piperidi2161''s(216-dioquinmorpholinomethyl)-1-piperidineacetic acid (prepared in Example 6) 4.0 g (10 mmol) (anhydrous N-methyl Add 3-21 (20 mmol) of 2-amino-1-(2°2-dimethyl-1,3-dioquinran-4-yl)ethanol (dissolved in 50 m of pyrrolidone) and heat to 60°C for 4 hours. After stirring for 16 hours at room temperature, the solvent was removed in vacuo and the residue was dissolved in diiso7°0 pyl ether 750 d.
Mix with...

The resulting precipitate is filtered and placed in 150 g of water.

Make a #9 solution with diluted hydrochloric acid (1), stir overnight at room temperature, and condense in X air. Stir the residue several times in diisopropyl ether, filter #9, and dry in vacuo. melting point 1
Colorless powder at 12-115°C 4.3. ! ii' (68% of theory) is obtained.

Analysis: Total 'li1 shift C46,94N7.09 N10
．． 95 measurement value C46, 71N7.18 N11.1
0 Example 6 2.6-bis(N,N-bis(carboxymethyl)-aminomethyl]-piperidineacetic acid 2.6-bis[N,N-
43.3 g (100 mmol) of bis(carboxymethyl)aminomethyl]-piperidineacetic acid were suspended in 300 WLt of water, and 18.13 g of gadolinium oxide was added. li'(50
mmol) is added. Heat to ioo'c for 3 hours, filter, and strain the filtrate in a makabe. The residue is dried at 60'C in a Makabe medium. Melting point is 320'C! High quality white powder 58
．． 19 (99% of theory) is obtained.

Ru.

Analysis: Calculation 1st shift C34,75H4,12K 7.15
oa 26.76 measurement value C64,62H4,27
The corresponding radioactive complex compound is obtained by reaction of the complex with gadolinium-156-chloride in a manner similar to "N 7.29 Gd 26.32-". In a similar manner, the complex former and indium-111-chloride (5m C1
10,1M) by reaction with the corresponding indium-11
A 1-complex compound is obtained.

Example 7 2.6-bis[:N,N-bis-(carboxymethyl)
Aminomethyl]-1-piperidineacetic acid gadolinium-
Mono-N-methylglucamine salt of 1-complex compound 2.6-bis(N,N-bis(carboxymethyl)aminomethyl]-piperidineacetic acid 8.67 g (20 mmol)
Milled in 5Qml of water and added 3.0ml of gadolinium oxide.
62.9 (10 mmol) is added. Heat to 100℃ and after 15 minutes N-methylglucamine 3-90g3-9O
mol) is added. Hold at 100"C for a further 2 hours, filter out a slight cloudiness, and boil the filtrate in a Makabe dish. The residue is transferred in vacuo at 60°C. A white powder with a melting point of 185-190°C. .251! (theoretical quantity 12)97'4) is obtained.

Analysis: #t'x value H5, 28N 7.16 Gd 20.
09 case foot f[H5,02N 7.01 0d l 9.
85 Example 8 2.6-bis(N,N-bis(carboxymethyl)amine methyl-two-piperidine in gadolini water 5-)
A suspension of 1.78.F (4.7 mmol) of bis-(N,N-bis(carzoxymethyl)aminomethyltwopiperidine) and 0-85 g (2.35 mmol) of gadolinium oxide was heated to 80° C. for 2 hours. In this case, by increasing the addition of D-(1)-N-methylglucamine (0.929 < 4.7 mmol), the value increased to 7.5. Subsequently, suction is drawn through a G4-glass frit, the bath liquid is evaporated in a rotary evaporator in the wall of a water-dead pump, and the residue is heated to 50° C. 3. lllllH
Dry at g. White powder with a melting point of 242-244°C3.
06g (89chi of Bi 1 theory) is obtained.

Analysis: tfn C36, 46H5, 63N 7.73 G
d 21.70 Measuring clay C3 (5,04H5,49N
7.62 oa 20.93 examples 9 2.6-bis(N,N-carboxymethyl-N-(2,
3-dihydroxy-N-methyl-propylcarbamoylmethyl)-7minomethyl]2,6-bis[N-carboxymethyl-N-(2,3-dihydroxy-N-methylpropylcarbamoylmethyl)-aminomethyl:]-] 1
- Piperidine acetic acid 15.2g 25mmol) in water 100M
Dissolved in acetic anhydride is trinium 8.4,! i'
(2.5 mmol) is cooled. Stir in a room for 6 hours, then mix the vinegar solution with anions first! 4 = Amber light (R)
I R410, and then in step 7, the liquid was passed through a cation exchanger Amberlite (R) I Rc51]. Rinse with water again, bath synovial fluid and crush in vacuo. Residue ■ After drying, colorless powder with melting point 218-220°C 16.6
g (71% of theory) is obtained.

Analysis: Calculate # C39,41H5,56N 9.19 G
d 20.64641j fixed 1 shift c 39.17
H5,70N 9.27 ad 20.50
Example 1Q 2.6-bis(N-carboxymethyl-N-[bis-(
2-Hydroxyethylrubamoyl]-aminomethyl)-1-piperidineacetic acid trinium complex compound bis(N-carboxymethyl-N-(bix-(2-hydroxyethyl)-rubamoylmethyl)-aminomethyl 1 7.6 g (12.5 m%) of -1-piperidine acetic acid was poured into 7 Q ml of water, and acetic anhydride was added to trinium 4.
2g (12.5mmol)? Add. After stirring at room temperature for 4 hours, the solution was added to the Vζ, m solution and the anionic desert body Amberlite (R) RA41f]. Separate the mixture with water and add the liquid to the cation exchanger Amberlite (R) IRC50.

The rice is ground in an aqueous syneresis solution and makabe, and the residue is dried. Colorless powder with melting point 212-216 °C 6.91 (theoretical amount 73
%) is obtained.

Analysis: Calculation 1st shift C39, 41H5, 56N9.19
Gd 20.64 (measuring value 1if C' 3
9.2.15 H5.40 N9.01
Gd 20.87 In a similar manner, the following can be obtained: 2.6-bis(N-carboxy-N-(bis(ethyl)
Gadolinium-complex compound of -rupamoylmethyl]-aminomethyl)-1-piperidineacetic acid: White powder analysis with melting point 230-234°C: ff'fR value C39,3f] H5,34N 1C
1,91Gd 24.50 measurement value C39,40H5,
44N 10.80 C) d 24.25 Gadolinium complex of 2.6-bis(X-carboxymethyl-N-[bis-(morpholinyl)-rupamoylmethyl]-7minomethyl)-1-piperidineacetic acid: Melting point 268~ White powder analysis at 242°C: #tX 1fc 40.38 H5,37N
9.81 Gd 22. C13 mountain 1j foot 1st shift C
40,50H5,51N 9.71 3a 22
．． 20 Example 11 2.6-bis[N-carboxymethyl-N-(2,3,
4-Trihydroxybutylcarbamoylmethyl)-aminomethyl]-piperizo2,6-bis[M-carboxymethyl-N-(2,3,4-trihydroxybutylcarbamoylmethyl)-7minomethyl]-1-piperidine acetic acid 18 .0 g (25rnmol)? 8.4 g (25 mmol) of trinium in acetic anhydride dissolved in 150 WLt of water
Add. After stirring at room temperature for 4 hours, the Sakai solution is first added onto the anion exchanger and cation exchanger as described in Examples 4 and 5, and the solution is subjected to /I:JMS in Makabe. After drying, it becomes a colorless powder with a temperature of 240-242'C.
(Theoretical amount (070%) is obtained.

Analysis: Calculation MC37,82H5,63N 8.82 o
a 19.81ζNIJ 11 C37,6
9H5,56N8.96 0d 19.62 Example 12 2.6-bis(N,N-bis(carboxymethylnoaminomethyl)-1-piperidineacetic acid is trinium-1-
Complex compound di-N-methylglucamine salt fIJ solution obtained in Production Example 1 2,6-bis(N,N-bis-c carboxymethyl)-aminomethylcou-1-piperidineacetic acid gadolinium-■- The complex compound 58.76 & (0.1 mol) is suspended in 40 ml of water (p,i,). Trome'thazin-hydrochloride (Trome'thazin-hydrochloride)
ochlorid) 0.189 and N-methylglucamine 39.11 (0.2 mol) in neutral
Add water (p, i,) f! to the solution. :Additionally 1oor
rt, fill the chamber 77', and place it in front of the heat wave.

Example 16 2.6-bis(N,N-bis(cal,oxymethyl)-
7minomethyl]-piperidine acetate ligadolinium-1-
293.8 g of gadolinium-1-complex compound of ceilidine salt of N compound
0.5 mol) is suspended in 500 ml of water (p,1-).

Lysine 292.4. ! i' (1 mol) was added, stirred for several hours under gentle heating, and then water (p.1.) was added.
Add to make 1oooy. Pour this bath liquid into a bottle and sterilize it by heating.

Example 14 2.6-bis(N,N-bis(carboxymethyl)-7
minomethyl]-1-piperidineacetic acid is trinium-1
- Sodium salt of complex compound 587.64 g (1
mol) in 500 ml of water (p,i,) to dlj4 and neutralize by addition of portions of 4'OJ/(1 mol) of caustic soda. After addition of 1.5 g of trometamino, the solution is added with X (p, 1.) to 1000 M, bottled and heat sterilized.

Example 15 Preparation of a solution of the gadolinium-I-complex compound of the conjugate of 2.6-bis(N,N-bis(carboxymethyl)aminomethylcy-1-piperidineacetic acid and human serum albumin) 0.5M! Sodium carbonate buffer 2+6-His(2°6-dioxomorpholino-methyl)-piperidineacetic acid 1 to a 20M solution of protein J3m9 in solution (p) 17.8)
Add 0rn9 (dimethylformamide Q, dissolved in 1 tnl). Stir for 30 minutes at room temperature and then dialyze against 0.3 molar sodium phosphate buffer. Gadolinium acetate-15[]η19 is then added and purified by Delchromatography on a Sephadex G25 column. Samurai Yureru Fraction? Sterile filter and fill into multivials. By extending the search, you can obtain the Inui-Lou prison sentence that can be stored. Gadolinium content: 1.8.

Using immunoglobulin r in a conventional manner, a solution of the corresponding compound conjugate with a gadolinium content of 1.1% is obtained.

A solution of the corresponding complex conjugate with a gadolinium content of 2.1% is obtained using hydroxyethyl starch in a comparable manner.

Example 16 Gadolinium-1-2,6-bis(N,N-bis-(carboxymethyl)aminemethyl]-piperidineacetic acid 4
Proc, Natl, Aca of subverted t liposomes
A lipid mixture of 75 mol% egg phosphatidylcholine and 25 mol% hycholesterol was prepared as a dry substance by the method described in d, Sci, U, S, A, page 75.4194. In this case, 500 m of diethyl ether and 30 m of water were placed in an ultrasonic bath.
0.1 mol of di-di-methylglucamine salt of gadolinium-1-complex of 2,6-bis(N,N-bis(carboxymethyl)aminomethyl-1-piperidineacetic acid) in p-1,) A solution of 6 M is added. After complete addition of bath D, sonication is carried out for another 10 minutes and then aged in a Rotavator.

The delta-like residue was suspended in 0.125M sodium chloride solution and centrifuged at 0°C (20,000 g/20 min).
By doing this, the large amount of contrast agent in the capsule is removed. Subsequently, the liposomes thus obtained are lyophilized in multivials. Application is 0.9% by weight
It is carried out as a colloidal dispersion in saline solution.

Example 17 Preparation of bath solution of yttrium-90-complex compound of conjugate of 2.6-bis(N,N-bis(carboxymethylnoaminomethyl)-1-1-piperidineacetic acid and monoclonal antibody) .05 molar sodium bicarbonate buffer (pi47-8)
2.6-bis(2.6-bis(
2,6-dioxomorpholine-methyl)-1-1-piperidineacetic acid 11η(dimethylformamide l), 011
Add 9 pieces of melted potato to 1V. Stir for 60 minutes at room width, 0.6
Dialyze against molar sodium chloride buffer. Then vinegar #I salt buffer (-6, Int, J, Appl,
Radiat, 1sOt, Volume 56 (1985) 80
Add 250 µm of 90Y-bath solution (manufactured on page 3) and incubate for 15 minutes. The solution is applied onto a combined Sephadex G25-column and the radioactive protein fraction is packed into multi-vials. Storage drying yields a storable dry formulation.

Example 18 Mono-N-methylglucamine salt of manganese-H-complex compound of 2.6-bis(N,N-bis(carboxymethyl)aminomethyl]-piperidineacetic acid 2.6-bis-1.J,N- Bis(carboxymethyl)
-aminomethyl]-1-piperidine vinegar 98.67g (2
0rn%k)'f: 1.41 (20 mmol) of manganese-II oxide (Mn05) suspended in 3Qml of water.
Add t. It is heated to 100° C. and after 3 hours 3.90 g (20 mmol) of N-methylglucamine are added. i'
Hold at o o'c for a further 12 hours, then concentrate the layer to dryness in vacuo. Quantitative yield, melting point 130-1
65°C (D rose color initial powder is obtained.

Analysis: Calculated value C42-29H6-21N 8.22 Mn
8.06 Measured value C42, 40H6, 10N B-5
1Mn 8.15 Example 19 2. Dysprosium- of 6-bis(N,N-bis=(carboxymethyl-aminomethyl)-1-piperidineacetic acid)
■-Complex compound Rimono-N-methylglucamine salt 2.6-bis-(N,N-bis(carboxymethyl)-
Aminomethyl]-piperidine acetic acid 8.6711 (20
mmol) is suspended in water 3omt+:P, and 3.73/(10 mmol) of dysprosium oxide is added. 100°
C and after 15 minutes N-methylglucamine 6.9
Add L17 (20 nmol). Still 5 at 100℃
Hold for Q and dry the CD liquid in vacuo. , ¥!
! l1 point 182~185'CO white powder 15.769
(100% of the theoretical amount) is obtained.

Analysis: Parking value C66, Ko8 H5, 24N 7.11
Dy 20.62 foot value C36,44H5,40N
7-21 Dy 21.501 Gadolinium 20 2.6-bis((N-carboxymethyl-N-impropoxycarbonylmethyl)-aminomethyl]-piperidineacetic acid 2.6-bis(2,6-dioxomorpholino Methyl)-1-piperidine vinegar IC Prepared in Example 3) 4, Og is heated under reflux for 5 Q with 2 Q ml of Impropatool. The mixture is then subjected to C condensation in vacuo, and the residue is heated to 100° C. with 1.82 (5 mmol) of gadolinium oxide in 100 M water until it becomes a clear liquid. Subsequently, the rr4 liquid is dried by bending. The product is 5oo-cyof)? It is observed as a white foam with a high melting point.

analysis:

Claims (1)

[Claims] 1. General formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, or represents a physiologically acceptable cation of an inorganic or organic base or an amino acid, where V^1 represents a group ^6
may be substituted with 1 to 5 hydroxy groups
saturated, unsaturated, straight-chain or branched-chain or cyclic hydrocarbon radicals having up to 1 or more C atoms
_6-dialkylamino group or by one or several C
_1-C_6- Represents an aryl group or aralkyl group which may be substituted with an alkoxy group, R^7 is a hydrogen atom, and 1 which may be substituted with 1 to 5 hydroxy groups.
represents a saturated, unsaturated, straight-chain or branched-chain or cyclic hydrocarbon group having up to 6 C-atoms, or R^6 and R
^7 together with one or several C_1-C_5-alkyl-, C_1-C_5-hydroxy-alkyl, C_2-C_6-acyl- which may be one hydroxylated or C_1-C_5-alkoxylated, hydroxy-
, carbamoyl-, carbamoyl-substituted C_1-C_6 -alkyl-, carbamoyl-C with 1 or 2 nitrogens
carbamoyl substituted by a _1-C_6-alkyl group (which can also form a ring with one oxygen atom), or substituted by one C_1-C_5-acylamino- or alkylacylamino group, One more
represents a saturated or unsaturated 5- or 6-membered ring which may contain up to 16 nitrogen-, oxygen-, sulfur atoms or one carbonyl group, and R^1^2 represents up to 16 C- Represents a saturated, unsaturated, straight chain, branched chain, or cyclic hydrocarbon group or aryl or aralkyl group having an atom, V^2- is a group X, ▲ has a numerical formula, chemical formula, table, etc. ▼, COOR^
1^2- or COB- group, where B represents a macromolecular group, R^1 represents a hydrogen atom or a CH_2X- group, and R^2 and R^3 represent a (CH_2)_m- group. , in which m represents 0 or 1, in this case R^4
and R^5 each represent a hydrogen atom, and R^4
and R^5 represents a CH_2-CH-(CH_2)_m- group, where m represents 0 or 1, and R^8 represents a hydrogen atom or R^9, where R^9 is imino-, May contain phenyleneoxy, phenyleneimino, amido, ester groups, oxygen, sulfur and/or nitrogen atoms and may be substituted by hydroxy, mercapto, imino and/or amino groups Straight-chain or branched, saturated or unsaturated, having one functional group at the terminal position or one macromolecule B bonded via this C_1~
C_2_0-alkylene group, in this case, R
^2 and R^3 simultaneously each represent a hydrogen atom; in this case, when V^2 represents a COB- group, R^8 represents a hydrogen atom, and when X represents a group PO_3HY, V with the proviso that ^1 and V^2 likewise represent PO_3HY]. 2. Claim 1 in which Y each represents a hydrogen atom
Compounds described in Section. 3,2,6-bis[N,N-bis(carboxymethyl)
-aminomethyl]-1-piperidineacetic acid, 2,6-bis[N,N-bis-(carboxymethyl)-aminomethyl]-piperidine, 2,6-bis[N,N-carboxymethyl-N-(2 ,3-dihydroxy-N-methylpropyl-carbamoylmethyl)-aminomethyl]-1-piperidineacetic acid, 2,6-bisN-carboxymethyl-N-
[Bis(2-hydroxyethyl)-carbamoylmethyl]-aminomethyl-1-piperidineacetic acid, 2,6-bis[N-carboxymethyl-N-(2,3,4-trihydroxybutylcarbamoylmethyl)-aminomethyl -1
-piperidineacetic acid, 2,6-bisN-carboxymethyl-N-[bis-(ethyl)-carbamoylmethyl]-aminomethyl-1-piperidineacetic acid, 2,6-bisN-carboxymethyl-N-[bis- The compound according to claim 1, which is (morpholinyl)-carbamoylmethyl]-aminomethyl-1-piperidineacetic acid. 4. At least two of the substituents X have atomic numbers 21 to 29,
42, 44, or 57 to 70 metal ion equivalents of at least one element. 5. At least two of the substituents X have atomic numbers 27 and 29,
The compound according to claim 1, which is a metal ion equivalent of at least one radionuclide of the elements 31, 32, 38, 39, 43, 49, 64, 70 or 77. 6. The compound according to claim 1, wherein V^1 and/or V^2 are each ▲a numerical formula, chemical formula, table, etc.▼- group. 7. The compound according to claim 1, wherein V^1 and/or V^2 are each a group X. 8, V^1 and/or V^2 are each COOR^1^
2. A compound according to claim 1, which is a 2-group. 9. The compound according to claim 1, wherein V^2 is a COB- group. 10. The compound according to claim 1, wherein R^1 is a hydrogen atom. 11. The compound according to claim 1, wherein R^1 is a group X. 12. The compound according to claim 1, wherein R^2 and R^3 are (CH_2)_m- groups, and R^4 and R^5 are each a hydrogen atom. 13. The compound according to claim 1, wherein R^4 and R^5 are ▲ groups having mathematical formulas, chemical formulas, tables, etc., and R^2 and R^3 are each hydrogen atoms at the same time. . Gadolinium-II complex of 14,2,6-bis[N,N-bis(carboxymethyl)-aminomethyl]-1-piperidineacetic acid, 2,6-bis[N,N-bis-(carboxymethyl)- mono-N-methylglucamine salt of gadolinium-II-complex of [aminomethyl]-1-piperidineacetic acid, gadolinium-II of 2,6-bis[N,N-bis-(carboxymethyl)-aminomethyl]-piperidine −
Complex N-methylglucamine salt, 2,6-bis[N,N
-carboxymethyl-N-(2,3-dihydroxy-N
-Methyl-propylcarbamoylmethyl)-aminomethyl]-1-piperidineacetic acid gadolinium complex, 2,
6-bisN-carboxymethyl-N-[bis-(2-hydroxyethyl)-carbamoyl]-aminomethyl-1
-Gadolinium complex of piperidine acetic acid, 2,6-bis[N-carboxymethyl-N-(2,3,4-trihydroxybutylcarbamoylmethyl)-aminomethyl]-
Gadolinium-complex of 1-piperidineacetic acid, 2,6-bisN-carboxy-N-[bis-(ethyl)-carbamoylmethyl]-aminomethyl-1-piperidineacetic acid, gadolinium-complex of 2,6-bisN- Carboxymethyl-N-[bis-(morpholino)-carbamoylmethyl]
-Gadolinium in aminomethyl-1-piperidineacetic acid-
complex, gadolinium-II complex of 2,6-bis[N,N-bis-(carboxymethyl)-aminomethyl]-1-piperidineacetic acid and human serum albumin, 2,6-bis[N, N-
Gadolinium-II complex of bis-(carboxymethyl)-aminomethyl]-1-piperidine acetic acid and immunoglobulin, 2,6-bis[N,N-bis(carboxymethyl)-aminomethyl]-1 -Indium-II-complex of piperidine acetic acid, 2,6-bis[N,N-bis-(
Gadolinium-II-complex of a complex of acetic acid and hydroxyethyl starch, 2,6-bis[N,N-bis(carboxymethyl)-aminomethyl]-1-piperidine Mono-N-methylglucamine salt of manganese-II-complex of acetic acid, 2,
Dysprosium-I of 6-bis[N,N-bis-(carboxymethyl)-aminomethyl]-1-piperidineacetic acid
mono-N-methylglucamine salt of I-complex, gadolinium-II-complex of 2,6-bis[(N-carboxymethyl-N-isopropoxycarbonylmethyl)-aminomethyl]-1-piperidineacetic acid, A compound according to claim 1. 15. General formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, Represents a physiologically tolerated cation of an amino acid, where V^1 represents the group
may be substituted with 1 to 5 hydroxy groups 16
saturated, unsaturated, straight-chain or branched-chain or cyclic hydrocarbon radicals having up to 1 or more C atoms
_5-dialkylamino group or by one or several C
_1-C_6- Represents an aryl group or aralkyl group which may be substituted with an alkoxy group, R^7 is a hydrogen atom, and 1 which may be substituted with 1 to 5 hydroxy groups.
represents a saturated, unsaturated, straight-chain or branched-chain or cyclic hydrocarbon group having up to 6 C-atoms, or R^6 and R
^7 together with one or several C_1-C_5-alkyl-, C_1-C_5-hydroxy-alkyl-, C_2-C_6-acyl- which may be one hydroxylated or C_1-C_5-alkoxylated , hydroxy-, carbamoyl-, carbamoyl-C_1 to C_6-
Alkyl-, carbamoyl- C_1 to C_6- with 1 or 2 nitrogens
carbamoyl- substituted by an alkyl group (which can also form a ring with one oxygen atom), or by one C_1-C_5-acylamino- or alkylacylamino group and substituted by another represents a saturated or unsaturated 5- or 6-membered ring which may have a nitrogen, oxygen, sulfur atom or one carbonyl group, and R
^1^2 is a saturated, unsaturated, straight-chained or branched or cyclic hydrocarbon radical or aryl- with up to 16 C-atoms
Or represents an aralkyl group, V^2 is a group X, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, C
OOR^1^2- or COB- group, where B represents a macromolecular group and R^1 is a hydrogen atom or CH_2X
- represents a group, R^2 and R^3 are (CH_2)_m-
Represents a group, in which m represents 0 or 1, in this case R^4 and R^5 each represent a hydrogen atom, R^4 and R^5 are ▲ mathematical formulas, chemical formulas, tables, etc. ▼Represents a group, where m represents 0 or 1, and R^8 is a hydrogen atom or R
^9, in which R^9 is imino, phenyleneoxy, phenyleneimino, amide, ester group,
straight-chain or branched, saturated or unsaturated, which may contain oxygen, sulfur and/or nitrogen atoms and which may be substituted by hydroxy, mercapto, imino and/or amino groups; C_1 to C_2_ having one functional group at the terminal position or one macromolecule B bonded via this
Represents a 0-alkylene group, in which case R^2 and R
^3 simultaneously represents a hydrogen atom in each case, and in this case V^2
When represents a COB- group, R^8 represents a hydrogen atom, and when X represents a group PO_3HY, V^1
and V^2 likewise represent PO_3HY], in order to produce physiologically acceptable complexes of the general formula II: ▲Mathematical formulas, chemical formulas, tables, etc.▼ by methods known per se. (II) [In the formula, R^2 and R^3 represent a (CH_2)_m- group, where m represents 0 or 1, and in this case, R^4' and R^5' each represent a hydrogen atom at the same time. Representation, R^4
' and R^5' are -CH_2-CH-(CH_2)_m
- represents a group, in which R^8' is a hydrogen atom or R^9'
in which R^9' optionally has imino, phenyleneoxy, phenyleneimino, amide ester groups, oxygen, sulfur and/or nitrogen atoms, optionally hydroxy, mercapto, imino and/or
or C_1-C_2_0-alkylene group having at the end a group that can be converted into a functional group contained in linear, branched, saturated or unsaturated R^9 substituted with an amino group], a ) phosphorous acid/formaldehyde or b) HalCH_2COOR^1^0 (where Hal
is chlorine, bromine or iodine and R^1^0 is hydrogen or an alkyl group having 1 to 4 carbon atoms), and subsequently an optionally present alkyl group R^ 1^0 is removed by saponification, and if desired, the resulting acetic acid-substituted compound is converted into compound III, IV or V: Yes▼(IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) [In the formula, R^1' represents a hydrogen atom or a CH_2COOH- group, R^1^1 represents a C_1-C_6-alkyl group, A and Z together represent an oxygen atom or A represents a hydroxy group and Z represents the group OR^1^1]
via reaction with an amine of general formula VI: There is ▼ (IIIa) by reacting the bis anhydride with alcohol R^1^2OH,
If desired, the acid of the general formula I [in the formula Y represents a hydrogen atom] obtained in this way can be prepared by a) a method known per se, with an atomic number of 21 to 29, 31, 3,
2, 38, 69, 42-44, 49 or 57-70 or 77 with at least one metal oxide or metal salt of the elements 2, 38, 69, 42-44, 49 or 57-70 or 77, and subsequently, if desired, the azide hydrogen atoms present are converted into inorganic and / or by substitution with an organic base or a cation of an amino acid, or b) by a method known per se, atomic number 21-29, 31, 3
2, 38, 39, 42-44, 49, 57-70 or 7
7 with at least one metal oxide or metal salt of the elements 7 and subsequently the metal complexes thus obtained can be reacted in a known manner via the functional groups contained in R^9' or with V^2 to the macromolecules with the CO- groups contained in the
or substituted by an organic base or an amino acid cation,
or c) bonded to the macromolecule by a method known per se via the functional group contained in R^9' or by a CO- group contained in V^2, and subsequently by a method known per se, with an atomic number of 21 to
29, 31, 32, 38, 39, 42-44, 49, 5
reacting with at least one metal oxide or metal salt of elements 7 to 70 or 77 and subsequently, if desired,
A process for the preparation of physiologically acceptable complex compounds, characterized in that the azide hydrogen atoms present are replaced by cations of inorganic and/or organic bases or amino acids. 16. At least one general formula I: ▲Mathematical formula, chemical formula, table, etc.▼(I) [In the formula, or represents a physiologically tolerable cation of an organic base or an amino acid, where V^1 represents a group
may be substituted with 1 to 5 hydroxy groups
saturated, unsaturated, straight-chain or branched-chain or cyclic hydrocarbon radicals having up to 1 or more C atoms
_6-dialkylamino group or by one or several C
_1-C_6- Represents an aryl group or aralkyl group which may be substituted with an alkoxy group, R^7 is a hydrogen atom, and 1 which may be substituted with 1 to 5 hydroxy groups.
represents a saturated, unsaturated, straight-chain or branched-chain or cyclic hydrocarbon group having up to 6 C-atoms, or R^6 and R
^7 together with one or several C_1-C_5-alkyl-, C_1-C_5-hydroxy-alkyl-, one hydroxylated or C_1-C_5-alkoxylated C_2-C_6-acyl-, hydroxy -, carbamoyl-, carbamoyl-C_1-C_6-alkyl-, carbamoyl-C_1-C_ with 1 or 2 nitrogens
Carbamoyl- substituted by a 6-alkyl group (which can also form a ring with one oxygen atom)
, or saturated or unsaturated 5 substituted by one C_1-C_5-acylamino- or alkylacylamino group and optionally having another nitrogen-, oxygen-, sulfur atom or one carbonyl group - or represents a 6-membered ring, and R^1^2
represents a saturated, unsaturated, straight-chain or branched-chain or cyclic hydrocarbon group or an aryl- or aralkyl group having up to 16 C-atoms, V^2 is a group X, ▲mathematical formula, chemical formula, table, etc. ▼ represents a COOR^1^2- or COB- group, where B represents a macromolecular group, R^1 represents a hydrogen atom or a CH_2X- group, and R^2 and R^3 represent (CH_2 )_m- group, in which m represents 0 or 1, in this case, R^4 and R^5 simultaneously represent a hydrogen atom, and R^4 and R^5 represent CH_2-C
H-(CH_2)_m- group, where m represents 0 or 1, R^8 represents a hydrogen atom or R^9, where R^9 is imino, phenyleneoxy, phenyleneimino, amide. -, ester groups, oxygen, sulfur and/or nitrogen atoms, hydroxy-
, straight-chain or branched, saturated or unsaturated, optionally substituted with mercapto-, imino- and/or amino groups,
Represents a C_1-C_2_0-alkylene group having one functional group at the terminal position or one macromolecule B bonded via this, in which case R^2 and R^3 each represent a hydrogen atom at the same time. In this case, when V^2 represents a COB- group, R^8 represents a hydrogen atom, and when X represents a group PO_3HY, V^1 and V^2 may similarly represent PO_3HY. A radiodiagnostic and radiotherapeutic agent containing a physiologically tolerable complex compound of the following conditions, optionally together with additives customary in galenic medicine.