DIAGNOSTIC MEANS

RK 397,465 B the FM'mdung refers to diagnostic means for application in the NMRbzw. Rfntgendiagnostik. Complex one and/or their salts since l gerem in the medicine used, so e.g. as aids to the administration badly 16slicher ions (e.g. iron) and of as antidote 0tierbeiwerden of calcium oderZink complexes bevomugt) for the Elatgiftung with inadvertent Inkorpomtion yon heavy metals or of them radiaktlven lsotopen. From the US-PS 4 176173 harm further verschiedone hafnium WAD tantalum Phosphon urekomplexe admits, which as radio-graphic Konla'asunittel ausschlieBlich fiir the oral application descriptive harm. Demgegenaber aims the available Erfmdung off to place diagnostic means to the Verfiigung which in particular ftir the parenteral application harm certainly. Hiebei is to berticksichtigen, dab the requirements to a Kontraslrnittel ftir the NMR diagnostics v611ig other one is zusatzlich than ftir a ROntgenkontrasunittel. Vorratmsetzung far those be suitable-likes a S toffes as Roentgen contrast means is its Fahigkeit, density variations between the damustellenden organ and the surrounding fabric to vergr0Bem, D, h. its slarkere (e.g. BaSO,) or schwtlchere (e.g. Air) absorption yon R6ntgenstrahlen Irish Republican Army comparison zurn K6rpergewebe. Usefulness its element as Roentgen contrast means htingt essentially yon the GrOge of its MassenabsorptionsKoefflzienten in the diagnostic S1rahlenbereich (as well as natiirlich its chemical-toxicological and phannazentischen own chaften) off. DieNMR diagnostics or Kemspin tomography is based against it on the physikalisehen Effect of the so-called Kem inremnanz (Nuclear Magnetic Resonance, NMR). Those, as diagnostic procedure erm6glieht it, longing CCIT pictures living bodies and Einbliek in Stoffweehselvorg uge zn receive R0ntgenstralfl-Diagnostik without Anwendun8 ioni ierender jets, like in animal. Atomic nuclei, - like hydrogen, show the Effela of the Kerru'esonarm which possesses magnetic moment in the biologisehen fabric of head ehlieh as water available istein and thereby in a strong iu ren Magneffeld align themselves. By a high frequency Impals (Resonanzf (equenz) wcrdcn it gebmcht from their Gleichgewlehtslage, into which sic with a charaktefistischen speed more winder zuriickkehren. The Darer of the Riickkehr in the Gldchgewichtsznstand, the so-called Rdaxation time, gives information fibre to the order liking degree of the atoms WAD more tiber their reciprocal effect with their Umgebuug. The figurative representation, which is one dureh the measurement of the proton density and/or the relaxation times erhall yon high diagnostic value WAD gives Ausknnft Tiber the water content and fibre the condition of the examined fabric. Thus tumor fabric shows for example lingerie relaxation times as gesmades comparison fabric. , Dab physiologically from the anion of a komplexbiIdenden Secure and to one or more Zentralion (EN) of an element of the ordinal numbers 21 to 29, 42, 44 or 58 to WAD if necessary or several physiologically harmless cation (EN) of an inorganic and/or organic base or Amino ure tiberraschenderweise was now found outstanding for the production of diagnostic Mitlel for application in the NMR diagnostics suitably sin& the subject of the invention is thus diagnostic in the middle, containing verlragliche complex salts at least physiologically vertr a gliches complex salt from the anion complex-forming S iure and one or more Zentralion (EN) of an element of the order liking numbers of 21 to 29, 42, 44 or 58 to 70 WAD if necessary or several physiologically harmless cation (EN) of an inorganic and/or organic base or Amino ure, if necessary with in the Galenik iblichen Zus tzen, in w serigem medium gel0st or suspends, to the Anwendtmg in the NMR diagnostics. The element of the above-mentioned ordinal number, which that or the Zentralion (EN) resembled physiologically vert complex salt more bolder. daft ftir the intended purpose desired erfmdungsgem of the iBen diagnostic means amplifier dlieh nieht radioactively its. In erfindungsgemaBen, for application in animal NMR diagnostics (see the Europtli patent application 71,564) means determined be muB the Zentralion of the complex salt paramagnetic. These are in particular zweiund the trivalent ions of the elements of the Ordnnngszahlen 21 to 29, 42, 44 and 58 to 70. Suitable ones lonen are for example the chrome (III) -, manganese (II) -, iron (III) -, iron (II) -, cobalt ('left) -, nickel (ll) -, copper (II) -, praseodymium (III) -, neodymium (In3, samarium (III) - and ytterbium (III) - ion. Because of their very strong magnetic moment alas Gadohnium (IlI) are particularly preferential -, terbium (Ill) -, dysprosium (III) -, holmium (l! I) - and erbium (III) - ion. A further article of the Erfindnng diagnostic means are containing, at least a physiologically vertrfigliehes complex salt to the anion of a complex-forming Stiure and one or more Zentralion (EN) of an element of the ordinal numbers 57 to 83 - excluded physiologically vertr a gliehes complex salt from the anion yon Ethylendiamintetramethylphosphohs ure or Diethylpenmmethylphosphonstiure WAD one or more Zentralion (EN) of tines element dcr ordinal numbers 72 and 73 - and if necessary one or mehremn physiologically harmless cation (EN) of a anorganisehen and/or organic base or Aminosaure, if necessary with in the Galenik iiblichen Zustitzen, in wtisserigem medium drawn or, for application in animal Roentgen diagnostics snspendiert. In the erfmdungsgemttfen, for application in the Roentgen diagnostics means intended muB alas Zentmlion see yon to an element h0herer ordinal number deriving, around a sufficient absorption animal X-ray to RK 397,465 B obtain. It gofunden, dab for this purpose diagnostic means, which vonElomenten a physiologically vertra_gliches complex salt along central ions the ordinal numbers between 57 and 83 contain, are suitable; these are for example the Lanthan0lD-ion, the above-mentioned ions of the Lanlhanidenreihe, alas gold (eyelid ion, alas Blci (ID-ion odor in particular bismuth (II1) - ion. As complex screen end S are suitable such uren, which one uses iiblichenveise for the Komplexbildung of the above-mentioned central ions. Suitable ones complex screen end sour one are for example such, which contain 3 to 12, vomugsweise 3 to 8 Methylenphosphon sgmre groups, Methylencarbohydroxamsaure groups, Carboxyethylidcngruppen or in particular Carboxymethylengruppen, yon those one, two or three to the Komplexbildung under tiitzendes handle toffatom in each case are bound. If three animal azides groups are bound to a Stiekstoffatom, then those are appropriate for the complex salts animal general formula II in accordance with Patentansprueh 2 and/or 4 underlying complex-forming S n'en forwards. Only in each case if elne or two the azides of the groups are to a nitrogen atom gebtmden, then the nitrogen is more tiber a if necessary substltuiertes ethyls or fibre bls to four, in each case by the Komplexbildung a tmterstiitzendes Stickstoffoder Sauerstoffoder sulfur atom separate Ethyleneinheitenan a further Stiekstoffatom gebunaen. Formally preferred complex screen end sour one this type sina such animal general I gemaB patent claim 2 and/or 4. The complex-forming Sattren k6nnen from Konjugate with Biomolektilen verkniipft warden, yon those admits itself is, dab it in the too tmtersuehenden organ or organ part to particularly anmichem. Such Biomolektilo harm for example hormones such as insulin, Prostaglandine, Steroidhcxmone, Aminozucker, Pepfide, proteins or Lipide. Particularly to emphasize Konjugatemit albumins, like human serum albumin, are AntikOrpem, wio to the Beispiol monoclonal far tumor-associated antigens speziftsche Antik0rper or Antimyosin. The diagnostic means formed from this are suitable for example zttr application in animal Tumorund Infarkt diagnostics. F Leberuntersuchangen are suitable for example Konjugate or EinschluBverbindungen with Liposomen, which are used for example as university-laminated odermultilamellarePhosphatidylcholin Cholesterol vesicles. The Konjugatbildung takes place either more tiber a group of carboxyls of the complex-forming Sure or in case of the proteins or Peptide anch fibre (CH2) a p-C6H4-WGruppe, as she is defmiert in the Patentansprueh 2 and/or 4. K0nnen with the Konjugatbildung of complex-forming S partial mehrem S uren iurereste to the macromolecular Biomolekiil to be bound with proteins, Peptiden or Lipiden. In this case can each complex screen end sour remainder a Zentralion tmgen. If the complex-forming sour ones are at Biomolekiile do not gebtmden, they carry for two central ions, in particular a Zentrallon if necessary. Suitable complex salts animal general formula 1 gemaB patent claim 2 and/or 4 are for example such the general formula X-CH2 /CH2-X N.CHRz.CHR3 _N V-CHR.]. CHR]. - V Oa), where X, V, g 1, R2, and R3 possess the meaning specified in the requirement 2 and/or 4. For the production of the complex salts of the general formula Ia the among other things following complex-forming S is suitable iuren: the Ethylendiamintetraessigs ure, the Ethylendiamintetraacethydroxamsaure, the trans l, 2Cy hexy endiamintetraessigs ure dieD -2 3-Buty endiamintetraessigsaure dieDL2-B ty endiamintetraessigsure, the DLL, 2-Propylendiamintetraessigs iure, the 1,2-Diphenylethylendiamintetraessigsllure, the EthylendiuitriloteWakis (methanphosphon ure) and the n (2-Hydroxyethyl) - ethyl diamine tri vinegar ure. Further suitable complex salts of the general formula I in accordance with Patentanspmch 2 and/or 4 harm for example such animal general formula Ib X'CH2 \ V-CHR i cycle per second-x N-CH x-CHZ (Z-CH2-C H.,) m-i \ CHRI_V Oh), RK 397,465 B w0rin X, V, Z, g 1 and m the 4 Bedeuttmg specified in the requirement 2 and/or possess. If Z means an oxygen atom or a sulfur atom, complex salts are mitm in animal Bedeuttmg yon 1 or 2 prefers. To manufacture-likes the complex salts of the general formula Ib are suitable see mould to other the following complex screen end sour one: the Diethylentdaminpentaessigsaure, the Tdethylentetraminhexaessigs iure, the Tetraethylenpentaminheptaessig Nm, the 13,23-Dioxo-15,18, 21-1ris (carboxymethyl) - 12.15.18.21 i24-penta-azapentatriaeontandis iure, the 3,9-Bis (1-carboxyethyl) - 3,6,9-triazamadeeandis ure, the Diethylentdaminpentakis (methylenphosphons ure), the 1,10-Diaza-4,7-dioxadecan-l, l, 10,10-tetraessigs iure trod the 1.10-Diaza-4.7-dithiadecan-l, l, 10,10tetraessigs ure. Suitable complex salts of the general formula I gemaB patent claim 2 and/or 4 are more femer such the general formula IC X-CH2 • t CH2 - X X-CH N-CH2-CH2-N CH C H 2 2 (CH2) (CH) w, 2 I CH2 _N/2 - \ CHz × (IC), where X and w possess the meaning specified in the requirement 2 and/or, 4. To the complex salts of the general formula IC is suitable inter other Siiuren manufacture-likes the following complex screen end: the 1,4,8,11-Tetraa7zcyclotetradecantetraessigs ure and in particular the 1,4,7,10-TetranT - cyclododecantetraessigstinre. Further complex screen end S tren, to the Herstellnng of the complex salts of the general formula I are suitable are for example: alas 1,2,3-Tris [to (carboxymethyl) - amino] - propane and the Nitrilotris (ethylennitrilo) - he.xaessigs ure. As example of a complex-forming Sure for ii-production yon complex salts of the general formula II the Nitrilotriessig ure is mentioned. If not all azides hydrogen atoms of the complex-forming Suture are replaced with the Zentralion or the central ions, it is more inorganic bases or Aminos organic for Erh6hung of the L6slichkeit of the complex salt zweckmaBig, the remaining hydrogen atoms dutch physiologically harmless cations and/or uren to substitute. Geeigncte inorganic cations are for example the Lithiumion, the Kaliumion or in particular alas Natriumion. Suitable cations of organic bases are inter other one such yon p n, sec. and arene or t n amines, like for example ethanol amine, Diethanolamin, Morpholin, Glucamin, N, NDimethylglucarnin more oiler in particular N-Methylglucamin. Suitable cations yon Aminosauren are for example those of the Lysins, Arginins or Omithins. F'tir the erf'mdungsgemaBe Mittd benStigten complex-forming sour one are well-known, or kSmaen in actually well-known way to be manufactured. Thus for example the production of the 13,23-Dioxo-15,18,21-tris (carboxymethyl) takes place - 12,15,18,21,24peamz7zpentatriacontan-disaure in improvement animal vonR. A. Bulmanet. Al inNaturwissenschaften 68. (1981) 483 vorge chlagenen Wise: 17.85 g (= 50 mMol) 1,5-Bis (2.6-dioxomorpholino) - 3-azapentan-3-essigsaure in 400 ml troekenem dimethylformamide suspended WAD after addition yon 20.13 g (-- 100 mMol) 11 - Aminoundecan iure 6 hours long auf70 °C erw irmt. The clear L6sung is restricted in the Vaknnm. The yellow 81ige Riiekstand is verriihrt with 500 ml Waster at ambient temperature. Nearly a weil3er voluminSser solid fiillt out, which will gewasehen sucked off and several times with Wa it. The receipt the ne product is goriihrt for further cleaning in 200 ml acetone ¢ingetragon and minutes at ambient temperature. After the starting from eyes WAD drying in the vacuum with 50 °C one orhalt 36.9 g (= 97% of the theory) of tines because) EN of powder of the fusion point 134 - 138 °C. The conjugation of the complex-forming Lauren with Biomolektilen effolgt likewise according to actually well-known methods, for example by reaction of nucleophiler groups of the BiomolektUs - like zurn example Amino, hydraulic XY, Thiooder Imidazolgruppen with an activated derivative of the complex-forming Same. As if akdvierte derivatives of complex-forming S iuren come beispiekweise g ureehlodde, g lureanhyddde, activated esters, nitrenes or lsothiocyanate into consideration. Turned around it likewise m6glich, an activated Biomolekiil with the complex-forming Siiure to convert. For the conjugation with proteins present themselves also gubstimenten to the structure - C6 I-I4 N2+ or C6 H4 NI-ICOCH2 halogen. RK 397,465 B the production of the complex salts is to the Tell likewise well-known or can in actually well-known way take place, by one alas metallic oxide or a metal salt (for example alas 16st or and equivalent with the password or suspension Mange of the complex-forming Sure in water and suspends nitrate, chloride or Sulfa0 of the element animal ordinal numbers 21 his 29, 42.44 or 57 to 83 in water and/or a low alcohol (like methanol, ethanol or isopropanol)! or a low alcohol shifts and riihrt, if required inter Erw mon or a heating up up to the Siedeptmkt, until the conversion is terminated. If the formed Komplexml7 is in the used L6sungsmittel unl6slich, it is isolated by Abf'dtrieren. If it is Itislich, then it can be isolated dutch evaporation of the L0sung to the Troekne for example mittens SprUhlroeknung. If aside groups are present in the received complex salt noeh, then zweekm industrial union is often, clas same complex salt by means of more inorganic and/or cxganischer bases or Aminos men, that form physiologically harmless Kafionen to isolate into neutral complex salts to iiberfiihren WAD these. In many F is this tllen unumgangllch, dale Dissociation of the complex salt by the Verschlebmag of the pH value to the neutral one so far is even zurtickgedrangt, thereby iiberhaupt only the Isolierang of uniform products or at least their Reinigtmg is made possible. Zweckm t igerweise takes place the Herstellang with the help of organiseher bases or basic Amino ttren. It can be however also favourable, the Neutralization rnittels anorganiseher bases (I-Iydroxiden, carbonates or Bicarbonaten) yon sodium to make potassium or lithium. To the Herstelltmg of the neutral lze one knows for example the sour complex lzen in more wgtBriger l.iisung or suspension as much the gewtinschten base to add, dal the neutral point is reached. The received password can be restricted anschlieBend in the vacuum to dry ones. H ufig is it the neutral salts formed by advantage, dutch Mugabe yon with water mixable L0sangsmitteln, like for example low alcohols (methanol, ethanol, isopropanol etc.), low Ketonen (acetone etc.), polar Ethem (tetrahydrofurane, Dioxan, 1.2-Dimethoxyethan etc.) anszuf'allen and soleichtzuisolierende and gutzu cleaning Kristallisatezu received. When particularly favourably has it proven, which einznsparen gewiinschte base w rend the Komplexbildung of the reaction mixture to already add and thereby a Verfahrensschdtt. If the sanren complex salts contain several free azides groups, then it is often zweekrn industrial union to manufacture neutral mixture salts which contain both inorganic from also organic physiologiseh unbedenldiche cations as Gegenionen. This can happen for example, by ilfte the complex screen end sour one in w of lBriger suspension or lsung with the oxide or salt the Zentralion of liefemden element and the H the quantity of a organisehen base bentitigten to the Neutralization converts, formed complex salt in an isolated manner, it gewiinsehtenfalls up-cleaned and then at vollst ndigen neutralization with the ben6tigen quantity inorganic base transferred. The sequence of the base addition can be also turned around. The production of the erf'mdmagsgemal3en means diagnostisehen effected likewise in actually well-known way, by one the complex salts gegebenenfaUs anter additive in the Galenik iiblichen to TZE in wgtl3figem medium suspended or 16st stefilisiert and ansehliellend the l sung or suspension. Suitable ones for TZE are for example physiologically harmless buffers (like for example Tromethaminhydrochlorid), small Z yon complexing agents (like e.g. Diethylentriamin pentaessigsaure) or if effordedich electrolytes (like e.g. Sodium chloride). In principle is miSglich cs anch to manufacture invention in accordance with Ben diagnostic means also without Isoliertmg of the complex salts. In each case muB special care on it to be used, the Chelatbildung so vorztmehmen, dab invention in accordance with n the salts and the Salzl0sungen are practically free yon did not komplexierten toxically working metal ions. This can be aware of-carried out for example with I-Iilfe yon color indicators such as Xylenolorange dutch for control titrations protecting the Herstelhmgsprozesses. The invention concerns from there also Veffahren to the I-Ierstellang of the complex connection and of their salts. As last security a cleaning of the insulating complex salt remains. Ffir if the oral administration or other purposes suspensions of the complex salts is erwiinscht in water or physiological Salzl0sung, a little is mixed 16sliches complex salt with one or more auxiliary materials and/or Tensiden and/or flavour materials tiblichen in animal Galenik to the Geschmaekskorrektur. Erfmdungsgem iBen diagnostic means the 1 pMol up to 1 mol per litre of the complex salt and usually in quantities yon 0.001 to 5 is contained preferably proportioned mMol/kg. They are intended for the oral and in particular parenteral application. The erfindtmgsgemgd3en means effiillen the vielfaltigen conditions f'tir the suitability as contrast means fttr the Kemspintomographie. Like that they are outstanding suitable for it, after oral or parenteral application dureh ErhShung of the Signalintensitht the picture received with the help of the Kernspintomographen in its force of expression for verbessem. Femer show it the high effectiveness, which is necessary to load in order gliehst the K0rper with m small quantities of foreign matter WAD the good VertrSgliehkeit, which is necessary, urn that not invasiven a character animal Untersuehung anfrechtzuerhalten (in J. Comput. Tomography 5,6: 543 - 46 (1981), in Radiology 144, 343 (1982) and in Brevet Special de Medicament No. 484 M (1960) indicated be-hired is RK 397,465 B for example too toxically). The good Wasserl0slichkeit invention in accordance with iBen means permits it to manufacture highly concentrated LOsangen to hold with it the volume load of the cycle within justifiable borders and to adjust the Verdormung by the KSrperfliissigkeit, i.e. NMR Diagnostika mtisren 100 to 1000-fach better water-solubly purely than fiir the NMR spectroscopy. Further point erfmdangsgemiil? , EN means nieht only high Stability in vitro, sondem also iiberraschend high Stabilitiit in vivo up, sodaB release or Austa_, mh animal in complexes does not kovalent bound actually poisonous ions within 24 Sttmden, in which - as pharmakologische investigations showed - the new contrast means indig again ausgesehieden become vollst, groove lul? , only slowly takes place. Those for example fOr the tumor diagnostics used Konjugate with proteins and AntikOrpem cause in so low dosage iiberraschend a high Signalverstgtrkung, here passwords according to low concentration to application to be already brought can. Erfindangsgem tl3en the means are outstanding as ROntgenkonWastmittel suitable, whereby particularly out. zuhebenist them no signs animal vondenjodhaltigen Konwastmittelnbekannten anaplaylaxieartigen reactions in biochemiscb pharmakologischen Untersachungen recognize itself along lasren. Particularly wertvoU they are because of the gfinstigen absorptive properties within ranges h6herer tubing tensions fiir digital Subtraktionsteclmiken. Irish Republican Army contrast to the conventional ROntgendiagnogtik with shade-giving Roentgen contrast means exists linear Abhiingigkeit the signal verse with the NMR diagnostics with pammagnetischen contrast means k¢in¢ rkung van the applied Konzentrafion. Like control investigations point, away an increase of the applizierten dose not necessarily to a Signalverstarkung, and it can come with a high dose at paramagnetic contrast means even to an extinction of the signal. It was for this reason iiberraschend, dab some pathological processes only after the Application higher than in the EP 71564 indicated doses (yon the 0.001 mMol/kg his to 5 mMol/kg amounted to can) of a strongly paramagnetic erfindangsgem 3en of contrast means becomes visible. As e.g. the proof of a defective blood-brain barrier within the range of a cranialen Abzesses can only after gift yon 0.05 - 2.5 mMol/kg, preferably 0, I - 0.5 mMol/kg yon paramagnetic complex salts as e.g. Gadolinium DiethylentriaminpenLaessiggaure and/or Mangan1,2-Cyc! ohexylendiamino tetrae gigsiium in form of their well water-soluble salts to be geFtihrt. FOr a dose gr6Ber as 0.1 mMol/kg are LOstmgen of higher concentrations to zn 1 Mol/1, vorzagsweise 0.25 to 0.75 MoF1 necessarily, since only so the Volaraenbelastung is lowered and the Handhabtmg of the Injektionsl6sung is it-carried out gew. Particularly low Dosiertmgen (under 1 mg/kg) and thereby lower concentrated passwords (1 IJMoFI his mMol/1) when in the EP 71564 are indicated, for the organspezifisehe NMR diagnostics z. tl to the proof yon Tamoren and yon cardiac infarcts needs. The following Ausfiihrungsbeispiele serves for the further Erlautemng of the F_M'mdung. I3ei piel 1 ii-production of the gadolinium III Kgmplox of the Nitrilg n, N, N-C-IE industrial union iur¢, C H GdNO5 the suspension yon 36 2 g (= 100 mMol) gadolinium oxide (Gd2 03) and 38.7. g (= 200 mMol) Nitrilola IO sig iur¢ in 1 2 litre water is gertihrt under Riihren on 90 degrees to 100 °C erwarmt and 48 hours with these Tom ratur. Then one filters fibre off Aktivkohlo yore unresolved ones and evaporates the filtrate to dry ones. Amo hel the Riickztand is pulvedsiert. Yield: 60 g; (87% of the theory) Fp.: 300 °C gadolinium: compute 45.5%, found 44.9%. The Risen III complex animal nitrile on, N, N-triessigs ure is received with FIilfe yon Risen III ehlorid, FeC13. B egg piel 2 blcrs llung de Di-Sodium salt de Gadolinium-III-Komplexes dcr 13.2 - Dioxo-15,18,21-tris (carboxvmethvl) - 12.15.18.21 .24-oentaaz oentatria¢ontan di ure, C36 _H_60 GdN5 _Q12 15,2g (=20 mMol) 13,23-Dioxo-15,18,21-tris (carboxymethyl) - 12,15,18,21,24-pentaaT pentatriacontan disaure are suspended in 400 ml Waster and erwiirmt on 95 °C. 7.43 g (= 20 mMol) gadolinium iii-chloride hexahydrate, gel6st in 60 ml water, are slowly zugelropft. 2 hours are held for LN caustic soda solution with these Tempemtur and shifted anschliel3end for the neutralization of the developed Salzsliure with 60 ml. After voUstandiger conversion (PrUfnng with Xylenolomnge) the received precipitation is chloride-free washed filtered and with water. One erh It 17.60 g (96% of the theory) of a wasserunl6slichen, weiBen powder yore Schmelzpankt 290 - 292 °C. Gadolinium iii-complex of the 13,23-Dioxo-15,18,21-tris (carboxymethyl) - 12,15,18,21,24-pentnaTapentatriacontandis iure. RK 397,465 B analysis: (Ber.) C 47.30 H 6.84 N 7.66 Gd 17.20 (gel.) C 47.13 H 6.83 N 7.60 Gd 17.06 14.6 g (= 16 mMol) of in such a way received gadolinium iii-complex are suspended in 200 ml water and shifted drop by drop with 31.4 ml LN caustic soda solution. After 1 hour one crhalt ein¢ clear Lssung, which is ftltdert and anschlie lp in the vacuum is restricted. After Troeknen in the vacuum with 80 °C one erlffdt 13.2 g (87% of the theory) one well wasserl6slichen, weil3en Pullers yore fusion point 279 - 285 °C. Analysis: (Pray.) C45,13 II 6.31 N7,31 Gd 16.41 Na4,80 (Gef.) C 45.20 H 6.12 N 7.28 Gd 16.26 well 4.75 in the same way becomes with N-Methylglucamln in place of Nalronlange the Di-N-Methylglucaminsalz of the gadolinium Ill complex of the 13,23-Dioxo-15,18,21-tris (carboxymethyl) - 12,15,18,21,24-pent 7 pentatriacontar Cs0 H96 GdN7 022 example 3 Hcr lcllung d¢ Di-Nalrium alz¢$ the gadolinium - iii-complex of the 3.9-Bis (1 - carboxvethyl) - 6-carboxvmethvl3.6.9-triazaundecandisaure. C1 6.U_22 GdN3 O1 36.2 g (= 0.1 mol) gadolinium iii-oxide and 84.2 g (= 0.2 mol) 3,9-Bis (1-carboxyethyl) - 6-carboxymethyl-3,6,9triaza-undecandisaure are suspencliert in 250 ml water and 1 hour to the Riickflul is heated up. One filtered yon few ungel0stem starting from WAD restricts those lot-likes Irish Republican Army vacuum to dry ones. The Riickstand is dried palverisiert and in the Yakuum with 60 °C. One receipt 112.8 g (= 98% of the theory) of the Chelats as because it powders. Analysis: C1 6H24 GdN301 0 (Ber.) C 33.39 H 4.20 (Gef.) C 33.25 H 4.49 Gd 27.32 N 7.30 Gd 27.42 N 7.21 57.6 g (-- 0.1 mol) of the Chelats into a password yon tznalron in 100 ml water are registered to 0.1 mol. Dureh addition yon further 0.1 mol of tznatron powder one steUt in the password a pH 7.5, heats the L0sang up for simmering trod drips up to the lasting T bung ethanol too. After mehrstiindigem Rfihren in the ice bath one sucks the Kristallisat off, wlkseht it with ethanol and dries it in the vacuum. One ert t in qanntitativer yield the DIN atrium salt as weighs powder. Analysis: (Ber.) C 31.02 H3,58 Gd 25.38 N6,78 (gel.) C 31.10 H 3.71 Gd 25.50 N 6.61 example 4 H¢r ell0ng of the Di-Morphglinsalze$ of the QadQlinium III Komulexes of the 3.9-Bis (1-carboxvethvD-6qarl? gxymethyl6,9-tdazaundecandisaure. C24. U.42 GdN 12 17.4 g (= 0.2 MOO Morpholin water gel0st becomes in 50 ml. One gives 3,9-Bis (1-carboxyethyl) to 42.1 g (= 0.1 mol) - 6-carboxymethyl-3,6,9-triazaundecandis ure and whereupon 18.2 (= 0.05 MOO gadolinium iii-oxide to WAD stop so long at R (ickfluB, until clear-draw-entered. Then one drips acetone to zttr lasting Tff, bung too. After mehrstiindigem Rfihren in the ice bath one sucks the Kristallisat off, w scht it with acetone and dries it in the vacuum. One erh It in quanfitativer yield the Di-Morpholinsalz as weirs powders. Analysis: (Ber.) C 38.44 H 5.65 Gd 20.97 N 9.34 (Gef.) C 38.31 H 5.72 Gd 20.76 N 9.32 example production of the Di-N-Methylglucaminsalzes of the gadolinium III Komplex¢$ dcr Diethvlentdamin n, N, N', N " j - uentaessi s ure. C28 H54 0dN5. Q20 39.3 g (-- 100 mMol) Diethylentriamin n, N, N', N ", N " - pentaessig ure is shifted in 200 ml water suspended WAD with 19,5 g (= 100 mMol) N-Methylglucamin. Ansehliel3end warden 18.12 g (= 50 mMol) gadolinium IlIoxid, Gd2 03, admitted by portion and the received suspension on 95 °C heated up. Sew approx. 1 Sumde shifts RK 397,465 B one with further 19.5 g (= 100 mMol) N-Methylglucamin WAD receipt after further 2 Smnden heating a clear password up. After vollstandiger conversion (control with Xylenolorange) by little Ungel0stem is filtered and the filtrate in the vacuum up to dry ones is restricted. The Riickstand is eingeriihrt emeut in 100 ml water drawn WAD in 250 ml ethanol. After mehrstiindigem Kiihlen one sucks the Kristallisat off, washes with cold ethanol and troeknetesbei 60°C in the vacuum. One erl t92,7 g (99% that theory) of a weigen powder with uneharaktedsfisehem Schrnelzpunkt. Analysis: (Ben) C 35.85 H 5.80 N 7.47 Gd 16.77 (GEL) C 35.50 H 5.72 N 7.20 Gd 16.54 for the cleaning of the complex salt can be used in place of yon ethanol likewise acetone, Propanol or Isopmpanol. Are kept accordingly: With dysprosium iii-oxide, DY203 Di.N Methylglucaminsalz of the dysprosium N complex of the Diethylentriamin n, N, N " j r', N " - pentaessigs; 4ure, C SI%4DyN5020: with lanthan iii-oxide, La2 03 Di-N-Methylglucaminsah of the lanthan iii-complex of the Diethylentriamin n, N, N', N ", N " - pentaessigs ure, C 8a54t 5O20; with ytterbium N oxide, Yb2 03 Di-N-Methylglucaminsah of the ytterbium iii-complex of the Diethylentriamin n, N, N', N ", N' pentaessigsfiure, C28H54YbN5020; with samarium iii-oxide, Sm2 03 Di-N-Methylglucaminsah of the samarium iii-complex of the Diethylentriamin n, N, N', N ", N " - pentaessigsaure, C28H54SmN5020; with holmium N oxide, Ho2 03 Di-N-Methylglucaminsalz of the holmium iii-complex of the Diethylentriamin n, NcN', N " ¢ ' - pentaessig ure, %sH54HoNsO20; with Wismnt M oxide, Bi2 03 Di-N-Methylglacaminsalz of the bismuth iii-complex of the Diethylentriamin n, N, N', N ", i'C' pentaessig ure, C28H54BiN5020: with gadolinium iii-oxide, Gd2 03 trichloroethylene N Methylglueaminsalz of the gadolinium iii-complex of the Triethylentelramin n, N, N', N ", N'", N'" hexaessigs; 4ure, C39 H78 GdN7 027 Femer receipt one: with holmium M oxide, Ho203 trod ethanol amine in place of yon N-Methylglucamin Di-Ethanolaminsalz of the holmium iii-complex animal Diethylentriamin n, N, N ", N ", N " - pentaessigslinre, C18H34HoNsO12: , with gadolinium rear oxide, Gd2 03 and Lysin in place of yon N-Methylglucamin Di-Lysinsalz of the gadolinium iii-complex of the Diethylentriamin n, N, N', N ", N " - pentaessigs iure, C26H48GdN7014Unter use of Diethanolamin alas Di-Diethanolaminsah of the I-Iolmium-III-complex that Diethylentriamin pentaessig acres, C22 H42 HoN5 014. The salts result as woman powders with uncharakteristischem Schmehpunkt. They are very well wasserl6sllch. Beisoiel 6 HersteUung t Di-N0trigmsghcs de gadolinium III Komplexe$ of the Dieth¥1entriamin-N, N, NKN ", N " - wntae gs over, C14 I-I18 Q4N3 010 18.2 g (= 0.05 mol) Oadolinium M oxide and 39.3 g (= 0.1 mol) Diethylentriamin pentaessigsaure are suspended in 110 ml water and 1 Sttmde to the Riickflug is heated up. The clear password is abgektihlt and brought by Mugabe yon approx. 80 ml 5 N soda-long aufpH 7.5. One heated up emeut for simmering WAD Iropft 250 ml ethanol too. After mehrsttindigem Rfihren in the ice bath one sucks the Kristallisat off, wfischt it with ice-cold ethanol and dries it with 60 °C in the vacuum. One erhfilt in quantitative yield a weiges powder, which sehmilzt bi 300 °C nieht. Analysis: (Ben) C 28.43 H 3.07 N 7.10 Gd 26.58 RKs 397,465 B (GEL) C 28.35 H 2.95 N 7.05 Gd 26.37 in appropriate way are received: with dysprosium iii-oxide, DY2 03 Di-Nalriumsalz of the dysprosium iii-complex of the Diethylentfiamin n, N, N', N ", N " - pentaessigsaare; C14HI8DyN3OI0 • 2 well; with lanthan AI oxide, La2 03 Di-sodium salt of the lanthan iii-complex of the Diethylentriamin n, N, N', N ", N " - pentaessigs iure; C14H18LaN3010 with Holiam III oxide, Ho203 Di-sodium salt of the holmium iii-complex of the Diethylentfiamin n, N, N', N ", N " - pentaessigsiiure; C14I-I18HoN3010 with ytterbium iii-oxide, Yb2 03 Di-sodium salt of the ytterbium iii-complex of the Diethylentdamin n, N, N', N ", N " - pentaessigsiiure; C14H18YbN3010 with samarium iii-oxide, Sm2 03 Di-sodium salt of the samarium iii-complex of the Diethylentdamin n, N, N', N ", N " - pentaessigsliure; C14H18SmN3010 with erbium Ill oxide, Er203 Di-sodium salt DOS of erbium iii-complex of the Diethylentriamin n, N, N', N ", N " - pentaossigsllure; C14H18EbN3010 • 2 well; with gadolinium iii-oxide, Gd, 203 sodium salt of the Di-gadolinium-III-complex of the Tetraethylenpentamin n, N, N', N ", N " '; NIV, NI¥ heptaessigsaure; C22H30Gd, 2N501 4 • well. This salvo fall as weil3es Palver with uncharakteristischem fusion point at WAD are very well wasserl6slich. Example 7 H r tellung de N-Methylglucamin alze8 de iron III Kgmplcx r Dialhvlentfiaminoentaessi ure. C21I-I37FeN4015 35.40 g (= 90 mMol) Diethylentriaminpentaessigs ure are shifted in 100 ml water suspended WAD with 24,3 g (= 90 mMol) Risen III CHLORIDE hexahydrate (FeC13 • 6 H2 0), gel0st in 100 ml water. Dark-brown suspension zunachst auf95 °C is heated up. After approximately 1 conditions changes itself the color in lightyellow urn. One adds ml LN caustic soda solution to 270 for the neutralization of the developed Salzs ure and heats further 3 hours up on 95 °C. The erhaltone lightyellow precipitation is sucked off, getroeknet washed with water chloride-free WAD in the vacuum with 60 °12. One erh lt 17.85 g (45% the.ode) its lightyellow Pullers, whose Schmelzpankt > °C is appropriate for 300. 17.85 g (-- 40 mMol) the erlaaltenen iron iii-complex in 200 ml water suspended WAD by portion with 7,8 g (-- 40 mMol) N-Methylglucamin, firmly, shifts. One erw trmt approx. 3 hours aaf 50 °C and receipt a nearly clear, rotbramae L6sung, which filtered and then in the Vakmam up to dry one is restricted. The Riickstand is dried with 50 °C in the vacuum. One erh lt 24.3 g (95% the Theories) its red-brown powder yore Schmelzpmakt 131 - 133 °C. Analysis: (Ber.) C 39.82 H 5.89 N 8.85 Fe 8.81 (GEL) C 39.70 H 6.00 N 8.65 Fe 9.01 with caustic soda solution in place of the organic base are received: Sodium salt of the iron iii-complex of the Ethylendiamintetraessigsliure, c1 0H12 FeN2 08 - well Nalriumsalz of the iron iii-complex of the trans l, 2-Cyclohexylen-diamin-tetraessig ure, C14H1 8FeN208 ° well Di-sodium salt of the Risen III complex Diethylentrinitrilo penta (methanphosphonsaure), C9H23FeN3015P5° 2 well sodium salt of the iron iii-complex of the 1,10-Diaza-4,7-dioxadecan-l, 1,10,10-tetraessigsaure, C14H20FeN2010 • well sodium salt of the iron iii-complex of the Ethylendiamintetraacethydroxamsaure, C10 H1 6FeN608 • well. In appropriate way become with N-Methylglucamin ertmlten: Di-N.Methylglncaminsalz of the iron iii-complex of the Diethylentriamin n, N, N', N', N " - pentaessig ure, C28I-I FeN5Og0 N-Methylglucaminsalz of the iron iii-complex of the tram1,2-Cyclohexylendiamin-N, N, N', N' tetraessigsiture; RK 397,465 B C21H36FeN3013 N-Methylglucaminsalz of desEisen lll complex of the Ethylendiamin n, N, N', N' tetraessigs ure, C17H30FeN3013 trichloroethylene N Methylglucaminsalz of the iron iii-complex of the Triethylentetramin n, N, N', N ", N'", N” - hexadecimal vinegar ttre, C39H78FeN7027. Using yon Diethanolamin ansteUe yon N-Methylglucamin becomes the Di-Diethanolaminsalz of the iron iii-complex of the Diethylentriamin n, N, N ", N ", N ", - acetic acid, C22H42FeNsO 14 pen received. Example 8 production of the N-Methylglueaminsalzes of the gadolinium REAR KomDlexes of the tmns-l.2-Cvelohexylendi rninN.N.N'. N' tetr essi ggaure. C21 H36 QdN3 013 20.78 g (-- 60 mMol) trans l, 2-¢yclohexylendiamin-N, N, N', N' tetraessig ure is suspended in 150 ml Waster. After Mugabe yon 11.7 g (= 60 mMol) N-Methylglucamin one erMlt a nearly clear stmg, to which 10.88 g (= 30 mMol) are given gadolinium oxide (Gd2 03). The again received suspension 6 St, nden erwarmt on 95 °C. One filtricrt yon few UngelSstem off and restricts the filtrate up to the Trockn¢. The Riickstand becomes in the vacuum with 60 ° (2 dried and pulverized. One erh ilt 38.6 g (92% of the theory) of a weiBen powder yore fusion point 258 - 261 °C. Analysis: (Ber.) C 36.25 H 5.22 N 6.04 Gd 22.60 (Gef.) C 36.40 H 5.50 N 5.98 Gd 22.52 in same way will receive the sodium salt of the gadolinium llIKomplexes trans1,2-Cyclohexylendiamin-N, N, N', N' tetraessigs ure, with Nalronlauge in place of N-Methylglucamin C 14H18GdN208 “well. M_it freshly gefalltem chrome III hy&oxkl, CR (OH) 3 becomes alas sodium salt of the chrome l! I-complex Ethylendiamin.N.N.N'. N' tetraessigs the ure, well receive c1 0H1 2CrN208. Beigpiel 9 ago tellung the Di-Natriumgalze$ deg manganese ii-complex of the trans l, 2y 10hexylendi min n, N] l' tetmeggigg ur¢. C1 18MnN208 " 2 N 34.6 g (-- 100 mMol) trans1,2-Cyelohexylendiamin-N, N, N " I' tetraessig ure warden under Stiekstoffin 100 ml water sus'pendiert and with 11,5 g (= 100 mMol) manganese ii-carbonate MnCO3, shifts. One heats auf95 up ° (2 and g t drop by drop 200 ml LN caustic soda solution too. The clear L6sung is dried in the vacuum restricted WAD of the Riickstandbei °C in the vacuum. One receipt 40.8 g (92% of the theory) of a rosafarbenen powder. Analysis: (Pray.) (2 37.94 H 4.09 N 6.32 Mn 12.40 (Gef.) C 37.78 H4,12 N6,20 Mn 12.31 in appropriate Wise are received: From copper ii-carbonate the Di-sodium salt of the copper ii-complex of the trans l, 2-Cyclohexylendiamintetraessigs iure, C14 H18 CuN2 08 • 2 well; alas cobalt ii-carbonate the Di-sodium salt of the cobalt ii-complex of the trans l, 2 (2yclohexylendiamintetraessigs ure, C 14H18C°N208 " 2 well; from nickel ii-carbonate the Di-sodium salt of the nickel ii-complex of the Iran l, 2-Cyclohexylendiamintetraessigs ure, C14 HI8 NiN2 08 • 2 well. With N-Methylglucamin in place of caustic soda solution wcrdcn crhalten: Di-N-Methylglucaminsalz of the manganese ii-complex of the trans l, 2-Cyclohexylendiamin-tetraessigsiture, C'28 H54MnN4018; Di-N-Methylglucaminsalz of the manganese ii-complex of the DL-2,3-Butylendiamin-tetraessigs ture, C26H52MnN408; Di-N-Methylglucaminsalz of the manganese ii-complex of the Etnylendiamin n, N, N', N' tetraessigs iure, (224H48MnN408; Di-N-Methylglucaminsalz of the manganese ii-complex of the DL-1,2-Butylendiamin-N, N, N', N' tetraessigs ure, C26H52MnN408; Di-N-Methylglucaminsalz of the manganese ii-complex of the DL-1,2-Propylendiamin-N, N, N', N' tetmessigs ure, C25HsoMnN408; RK 397,465 B trichloroethylene N-Methy g ucaminsa zdesMangan I - K MP of exes erDiethy entriamin pentaessigsaure c35H72MnN6 25; with nickel ii-carbonate, NiCO3 Di-N-Methylglucaminsalz of the nickel ii-complex of the Ethylendiamin n, N, N', N' tetraessigsaure, C24H48NiN4O 18; with cobalt ii-carbonate, CoCO3 and ethanol amine Di-Ethanolaminsalz of the cobalt ii-complex derEthylendiamin' N, N, N', N' tetraes, sigNur C14 H28 CoN4 010; with, CuCO3 and ethanol amine Di-Ethanolaminsalzdes Kupfer-II-Komplexesder Ethylendiamin n, N, N', N' tetraessigNure, copper II earbonat C14 H28 C 4 0 lff with manganese II earbonat, MnCO3 and Diethanolamin trichloroethylene Diethanolaminsalz of the manganese ii-complex of the Diethylentdamin n, N, N', N ", N " - penmessigstiare, C26H54MnN6016; with manganese ii-carbonate, MnCO3 WAD Morpholin Di-Morpholinsalz of the manganese ii-complex of the Ethylendiamin n, N, N, N " - tearae, ssigsiture, C 18H 32MnN 4° 10 " Beis iel N-Methvl lucaminsalz ₜ les Go lglini m-III-KgmDlexes of the Ethylendiamin n, N, N', N' I Wd} sig 81 r C17 _3eCON3013 29.2 g (= 100 mMol) Ethylendiamin Nkff, N', N' tetmesslgstiure are heated up in 100 ml water suspended WAD with 18,1 g (= 50 mMol) gadolinium iii-oxide, Gd203, auf95 °C. Protecting heating • N-Methylglueamin are admitted by portion to 19.5 g (= 100 mMol). One erlaalt nacla approx. 3 stood a glare L0sung, which is fillriert and restricted in the vacuum up to dry ones. The RUekstand is gelrocknet in the vacuum with 60 °C. One receipt 61.3 g (95% animal theory) its because EN Pullers with uncharakteristisclaem SehmelzpunkL analysis: (Ber.) C 31.82 H 4.71 N 6.55 Gd 24.51 (Gef.) C 31.65 i! 4.59 N 6.52 Gd 24.56 in similar Wise is received: With dysprosium lll oxide, DY2 03 N-Methylglueaminsalz of the dysprosium iii-complex of the Ethylendiamin n, N, N', N' tetraessigstiure, C17I-I30DYN3013; N-Methylglucaminsalz of the gadolinium iii-complex that l, 10-Diaza-4,7-dioxadecan-l, l, 10,10-tetraessigsaute, C21 H38 GdN3 015; N-Methylglucaminsalz of the Gaclolinium III KompIexes of the 1,2-Diphenylethylendiamino-tetraessigsaure, C29I-I38N3013Gd; with lead ii-oxide, PbO and sodium hydrochloride Di-Natdnmsalz of the lead n complex of the Ethylendiamintelraessigsaure, C10 H12 N2 OsPb • 2 well; with freshly gef illtem chrome iii-hydroxide, CR (OH) 3 sodium salt of the chrome iii-complex of the Ethylendiamintetraessigs ure, c1 0H12 CrN2 08 • well; and similar to sodium salt of the gadolinium iii-complex the Ethylendiamin tetmacethydroxamsaure, C10 H16 GdN6 08 • well; Sodium salt of the gadolinium lII complex of the Ethylendiamin n, N, N', N' tetmessig ttre, c1 0H12 GdN2 08 • well. Example 11 Herstellun D derlA.7.10-TetraaTac cl - N ““” - tetraessi s ure. C16. H24. Q [28 • N 4,0g (= 10mMol) 1,4,7,10-TetraaTzcyclododecan-N, N'k “, N” - tetraessigsaurewerden in 20 ml water suspended and with 10 ml LN-Nalronlauge transferred. 1.8 g (= 5 mMol) are h'mt gadolinium IlI oxide, Gd2 03, zugegoben and the suspension 2 hours on 50 °C erw. The clear password is filtered and restricted in the vacuum. The Riiekstand is dried and pulverized. One erhtilt 5.5 g (95% of the theory) of a weil3en Pullers. Analysis: (Ben) C 33.10 H 4.17 N 9.65 Gd 27.08 (gel.) C 33D1 H 4.20 N 9.57 Gd 27.16 in same Welse is received: N-Methylglucaminsalz of the gadolinium iii-complex of the 1,4,7,10-Tetraazacyclododeean-N, N', NV', N'" RK 397,465 B tetra ssigsaure, C23 H42 GdN5 013 sodium salt of the gadolinium iii-complex of the 1,4,8,11-Tetmazacyclotetradecan-N, N', N “, N” - tetraessigstiure, C18H28GdN408 • well. Beis'p_ iel 12 production t T9Wd-N-Methylglucaminsalze$ of the gadolinium lTI Komolexes Ethvlendinitrilo tetr ld (methanDhosohons ure). C34 .HH85GdN6. Q32_P.4 9.11 g (= 20 mMol) Ethylendinitrilo tewakis (methanphosphonstiure) are eingesteUt in 150 ml water suspended WAD with the appropriate quantity of N-Methylglucamin a pH value yon 5. One gives gadolinium Ill oxide, to 3.6 g (= 10 mMol) Gd203, to WAD erwtirmt auf70 °C. After approximately 1 hour receipt one a clear L6sung, which with the remainder-borrowed rope to N-Methylglucamin one shifts. Altogether 15.6 g (= 80 mMol) N-Methylglneamin are verbraueht. The L6sung is restricted in the vacuum up to dry ones and to the remaining gel-like Rtiekstand in 200 ml acetonitrile is registered. Approx. 20 hours are sucked off with 30 °C geriilm and animal received fine precipitation. After drying in the vacuum with 40 °C receipt one 23.4 g (85% of the theory) of a weiBen powder veto Sehmelzpunkt 115 - 118 °C. Analysis: (Ber.) C 29.78 H 6.25 N 6.13 P 9.04 Gd 11.47 (gel.) C 29.85 H 6.57 N 5.98 P 8.78 Gd 11 26 in gleieher way are received: Hepta N Methylgl ucaminsalz the gadolinium iii-complex of the Diethylentdamin - N, N, N', N ", N " - penta (methanphosphonsiture), C5gH1 44GdN10 050 P5; and unmr yon caustic soda solution turn-likes C9H236dN3015P5 in place of N-Methylglueamin Di-sodium salt of the gadolinium iii-complex Diethylentrinitrilo penta (methanphosphonstture), • 2 well. Example 13 I-Ier tell ng the Di-sodium the alzes manganese ii-complex Eflaylendinitrilo telra (aeethvdroxam iure). 16MnN6.Q.O8 • 2 well 2.30 g manganese II earbonat and 7.05 g Ethylendinitrilotetra (aeethydroxamsaure) in 18 ml water 3 hours ztnn Rtieldlug is heated up. Then one steUt darch Mugabe yon more verdiinnter soda-long on pH 7 and adds drop by drop 40 ml Aeeton. Sew mehrstiindigem Riihren in the ice bath sucks one the separated Kl-istallisat off, w ischt it with acetone and dries it with 50 °C in the vacuum. One erhtilt in quantitative yield a Dihydmt as because] it powders with one above 300 °C lying fusion point. Mn: (Pray.) 11.30 (Gef.) 11.12 B i iel 14 Herstellun of a Mischsalzl6sung to Natriumund the N-Methylglucaminsalz of the Qad01inium-IIi of complex Diethvlentriamin pentaessi the sfinre a) Herstellnng v0m mono N methylglucaminsalz the complex, C 21! - I37 QdN4 015 195.2 g (1 mol) N-Methylglucamin become in 71Wasser gel6 t. Then one sett 393.3 g (1 mol) Diethylentriaminpentaessig ure and 181.3 g (0.5 mol) gadolinium oxide, Gd2 03, too and heats 2 S up mnden to R ieldlul], those f'fltriertg ldare L6sung is sprtihgetroeknet. One erhtilt because] it a crystalline powder with a water content yon 2.6%, D with 133 °C sint blanks and with 190 °C under Aufschiiumen melts. Od: (Ber.) 21.17 (gel.) 21.34 1) HersteUung of the neutmlen Mischsalzl0sung 730.8 g (= 1 mol) the mould a) of the received salt becomes in 630 ml water p. i.* suspended WAD g by portion (= 1 mol), tznatron powders zngeftigt. The nemrale L0snng becomes with water p. i. anf 1000 ml anfgefiillt, more tiber a Pyrogenfilter in bottles abgefitllt and heat-sterilizes. This I-molecular L6sung enthiilt 753.8 g Misehsalz pm litres. RK 397,465 B I-Ierstellun g of a L6sun Di-N-methvl of the lucaminsalzes the gadolinium - III-K0mplexe that hyl ntri nlnpentaessi the s, Iure 535.0 g (-- 730 mMol) in the example 5 besch iebenen salt becomes in 500 ml water p. i. angesclfl mmt and dutch addition yon 142.4 g (= 730 mMol) N-ME ylglucamin with pi-i 7.2 in L isung gebr ht. Intestine becomes with water p. i. on 1000 ml aufgeffillt, the L6s ng in Amptfllen abgefgllt and hitzestefilisierc Beigoiel 16 I-Ier tellun a Lsgun of Di-sodium salt deg gadolinium III Komplcx¢ of the Di thylenMamin t entaesslgsure 485.1 g (= 820 mMol) in with iel 6 received Di-Natrittmsalzes warden in 500 ml Wasserp.i. angesehl nmt. Then becomes with Waster p. i. on 1000 ml aufgeffiUt, those IASsung in ampuls abgefiillt and heat-sterilizes. * p. i. = per injectione Beisoiel 17 Herstellun of a L0stmg of the Di-sodium salt of the gadolinium III KomNexes animal 13.23-Dioxo15.18.21-tris (earboxvmethvl] - I 2.15.18.21 .24-oentaaza ntatriaeontandis ure 392.0 g (= 400 mMol) of the salt described in example 2 become in 500 ml Waster p. i. angeschl and nmt dureh Auffiillen with Waster p. i. on 1000 ml inter easy Erwarmen gel6st. The IAisung is abgef'gllt and heat-sterilized in bottles. Beisoiel 18 Herstellun of one sun desN Methvl of lucaminsalzes desGadolinium III KomNexes of the 1A.7.10-TetraazacvclododeeanteWaessi s ure 370.9 g (= 500 mMol) of the salt aufgeffihrten in example 11 become in 500 ml water p. i. angescNiimmt and dutch Aufffillen with water p. i. on 1000 ml gel6st. The l sung is ampulliert and heat-sterilized. Example 19 I-Iemtolhm of a Bosun g DOS Di-N-Methvlglucaminsalzes DOS Mangan-ll-K0mplexes animal tran - 1,2-Cv¢lohexvlen tiamintetrae industrial union ur¢ 395.9 g (-- 500 mMol) the salt aufgefiihrten in example 9 becomes in 500 ml water p. i. suspends. One transferred with 1,3 g Aseorbins ure WAD brings dureh Auff illen with water to p. i. on 1000 ml in IASsang. The Efsmag is sterile-filtered and abgefiillt in Ampnllen. Beisp_ ie120 production of a Issuing of the trichloroethylene N Methylglueamin alze d¢ manganese ii-complexes of ler Dielhvlcntriitrninoentaessig urg 514.4 g (= 500 mMol) of the salt aufgef'tthrten in example 9 become in 600 ml Waster p. i. saspendiert. One shifts ure and 16st with 1,3 g Aseorbins dutch Aufftillen with water p. i. on 1000 ml. The sterile-filtered l sang in ampuls is angeffiUt. Example 21 ii-production of one l.JSsung DIN methyl the lucaminsalzes Eisen-III-K0mplexe of the Diethylentriaminpent e industrial union ure 44.6 g (= 0.1 MO1) of the iron iii-complex Diethylentriamin pentaessigs the ure received in example 7 become in 40 ml Wasserp. i. suspends. After Zngabe yon 0.18 g Tromethamin I Iydrochlorid and 39.1 g (= 0.2 mol) N-Methylglucamin gel0st, the L0sung along water p becomes neutral. i. on 100 ml aufgeffillt, in ampuls abgeFtfllt and heat-sterilizes. BeisNe122 production of a l_2) ang de Qa t01inium-III-K0mplexes of the Nitrilgtrie industrial union RH 1.9 g (= 10 mMol) Nitrilotriessigs ure WAD 1.8 g (= 5 mMol) gadolinium iii-oxide become in 100 ml water p. i. under Erw gel6st men. The I sung one ampulliert and one heat-sterilizes. With iel 23 I-Ierstellun of a Lfsun of the N-Methvl the lucaminsalzes gadolinium III KomNexes of the Ethylendiarnintetraessig lr¢ RK 397,465 B 38.52 g (= 60 mMol) of the substance described in Beispie110 water p becomes in 70 ml. i. gel0sL after Mugabe yon 0.12 g Tromethamin becomes with Waster p. i. on 100 ml aufgeftillt, those L0sung in ampuls abgemllt and heat-sterilizes. With ie124 ell ng liners L0$ ng D Di-N-Methylglucaminsalzes the dysprosium iii-complexes D r Dieth¥1entriamin ntaessi s iure 35.7 g (= 60 mMol) of the dysprosium iii-complex the Diethylentriamin pentaessigsaure (water content 8.0%) warden ago in 70 ml water p. i. suspends and by additive of 212 g (= 120 mMol) with pi-i 7.5 brought N-Methylglucamin in I.aSsung. Then becomes with water p. i. on 100 ml aufgef'tillt, those L6sung ampulliert and heat-sterilizes. BeisDiel Herstellma liner L0 un the N-Methvl of the lucaminsalzes gadolinium iii-complex of the trans-l.242vclohexvlendiamin-tetraessi gre 555.8 g (= 0.8 mol) of the salt described in example 8 become in water p. i. to 1000 ml drawn. After filtration fibre a Pyrogenfilter is abgeffillt and heat-sterilized the password in ampuls. Beisoiel 26 I-Ier tell0ng of a IA ung the N-Methvlglneamin alze de Ruthenium-III-K0mplexe$ of ter 1,1O-Diilz -4.7 - $ithiadeean l, l, l Q, 10-tetraessigsiiure 15.6 g (= 0.03 mol) of the ruthenium iii-complex of the 1,10-Diaza-4,7-dithiadecan-l, l, 10, I0-tetraessigs ure water p becomes in 50 ml. i. suspends and by Mugabe yon 5.9 g (- 0.03 mol) N-Methylglucamin with pit 7.5 in IASsung brought. One f/Jilt with water p. i. on 1000 ml up, the I.aSsung in ampuls ftillt and heat-sterilizes it. With iel 27 ellung a Losun g of the Di-Lysinsalzes of the Gadolinium-III-K0mplexes e i g 0re 273.8 g (= 0.5 mol) of the gadolinium III Complexes animal DiethylenWiamin pentaessigsfiure warden in 500 ml water p Diethvlentriarnin pent ago. i. suspends. One admits 292.4 g (= 1 mol) to Lysin, l t melarere Stmaden under schwaehem Erw rnen n] hren and ftillt then with water p. i. ad 1000 ml up. The password is abgeFdllt and heat-sterilized in bottles. With i¢l 28 ago division of a L0sung of the trichloroethylene N Methylglucaminsalzes of the Moldavian VI KQmplexe of the DioIh¥1gnl; ri - ninI entaes igs ur¢ 18.8 g (= 0.28 mol) of ties complex H3 [Mo202 (OI-I) 4 • C14H23N3O 10] water p becomes in 50 ml. i. suspended and dureh addition yon 16.4 g (= 0.84 mol) N-Methylglucamin gelSst neutrally. One admits 0.15 g Tromethamin, ffillt with Wasmr p. i. on 100 ml up, the L6smag of a sterile filtration WAD subjects fiillt it in ampuls off. l ice iel 2P H r ng eider IASsung D of Di-sodium salt of the manganese II Komplex¢ of the Ethylendiamin tetrae industrial union ur 343.2 g (= I mol) of the manganese ii-complex Ethylendiamin tetraessigs the ure water p becomes tell in 500 ml. i. lmndi blank and duroh Imrtion, swoi o Zugabo yon 80 g (- 2 mol) Atznatron neutrally gcl0st. After Mugabe yon 1.5 g Trom thamin the password with water p becomes. i. ad 1000 ml aufgefiillt, in bottles abgeffillt WAD heat-sterilizes. Beisoiel ago tellung a L0sung 0as of sodium salt of the Eisen-III-K0mplcxes Ethvlendiarnin tetraessigs ure 345.7 g (= 1 mol) of the iron iii-complex the Ethylendiarnin tetraessig ure warden in 500 ml Waster p. i. SUSlmndiert WAD through portio weige addition yon 40 g (= 1 mol) tznatron gelSst neutrally. Sew addition yon 1.5 g Tromethamin becomes the L0sung with water p. i. ad 1000 ml aufgeffillt, in bottles abgefrillt and heat-sterilizes. Beis ie131 H r tellun a L0sung of the Di-sodium salt of the iron! Ii-complex Diethvlentriamin pentaessigsaur of the 334.6 g (= 0.75 mol) of the iron iii-complex the Diethylentriamin pentaessig ure water becomes p in 500 ml. i. suspends and darch Mugabe by portion of 60 g (= 1.5 mol) tzna on neutrally gel0st. L sung becomes with water p. i. ad 1000 ml aufget'tillt, in bottles abgefiillt and heat-sterilizes. Beisoiel 32 Herstellun g einerL0sung de Natriumsalzes of the gadolinium iii-complex of the trans1,2-C¥clohexylendiamin etraessigs ure I5… RK 397,465 B 558.6 (= 1 mol) of the salt specified in example 8 become in water p. i. ad 1000 ml gel0st. The l sung is abgeftillt and heat-sterilized in bottles. Beigoiel 33 Herstollan zeinerLOsun g! ¢sN Mcthyl lucamin the alzes Oadolini of the lm-llIKomolexes 1.2-Diohenvlethvlen left lminWWaessi ure 396.9 g (= 500 mMol) of the salt described in example 10 become in 600 ml water p. i. angeschlammt and dutch Auffiillen on 1000 ml gel6st. The L6sung is abgefiillt and heat-sterilized in ampuls. Beisoiel 34 Herstell0ng liner l 0ng de Natrium alze de Eisen-HIK0molexes Ethvlendiamin tetraessi of the s ure 183.5 g (= 500 mMol) of the $alzes specified in example 7 become in 500 ml water p. i. angeschl nmt. One adds 1.0 g Tromethamin, ftillt with water p. i. on 1000 ml up, ftillt those lot-likes in ampuls starting from and hitzestedlisiert. Beisaiel Herstellong liner L6sung of the Di-N-Methvlglucaminsalzes of the lanthan III Komt of the lexes Diethvlentriaminpentaessi s ure 459.8 g (= 500 mMol) of the salt aufgefiihrten in example 5 become in 650 ml water p. i. angesehlganmt and by Auffiillen with water p. i. brought on I000 ml in Lfisung. One fiillt the L6sung in ampuls starting from and hitzestedlisiert. Beisoiel of 36 ago ellung liners password d¢ Di-N-Methvlglucaminsalzes the bismuth iii-complexes that [hvlentriarnint entaessi ure 692.8 g (= 700 mMol) of the salt aufgefiihrten in example 5 warden in 600 ml water p. i. angese mt and after addition yon 1.8 g Tromethamin by Auffiillen with water p. i. on I000 ml under easy Erwarmen gel6st. The LtSsang is heat-sterilized in AmpuUen abgefiillt and. Beisoie137 Hcr tcll tn liner L6sung D Di-N-ME hvlglucaminsalze$ the H01mium-III-K0mPlexes of the Diethvlentriaminpentaessi ure 662.0 g (= 700 mMol) of the salt aufgeftihrten in example 5 become in 600 ml water p. i. angesehl and anmt after addition yon 1.8 g Tromethamin darch Auffiillen with water p. i. on I000 ml inter easy Erwarmen gelSst. The password is abgefiillt and heat-sterilized in ampuls. Beisoiel 38 Hersl; ellun a L0surt ¢S Di-N-Mothvl gl caminsalzes Y ((erbium III Komolexes of the Diethvlentriamin0entaessi sour 476.9 g (= 500 mMol) in example 5 aufgef kinds of salt become in 650 ml water p. i. angeschl and after addition yon 1.5 g Tromethamin anmt darch Aufffillen with water p. i. anf 1000 ml drawn. The I..6sung is heat-sterilized in ampuls abgef'tillt and. Beisoiel 39 Hcr tellung liner LO of ungdes Di-well umsalzes de LanthandlI-K0mvlexes of the Diethvlentriamin t ntaessi ure 573.2 g (= 1000 mMol) of the salt aufgefiihrten in example 6 become in 650 ml water p. i. angeschl nmt and by Auffiillen with water p. i. on I000 ml gelfst. The L6sung is hitzestexilisiert in ampuls abgeffillt and. Beisoiel 49 Hcr l ell ng a L0sung de Di-Sodium salt of the Dysprosium-IlI-K0mplexeg animal Dieth¥1enlTi; unin pent - essi sour 477.4 g (= 800 mMol) of the salt aufgeftihrten in example 6 become in 600 ml water p. i. angesehl anmt and by Auffiillen with Waster p. i. aaf 1000 ml gel6st. The I snng in ampuls one abgeftillt and one heat-sterilizes. Beisoiel 4I H0r ¢ll ng einerl., 0sun g of the Di-Natricm salze8 de Hglmiom III Komplex¢ lCr Diet, hylcntriamin t ntaessi ate 299.6 g (= 500 mMol) of the salt aufgefiihrten in example 6 in 500 ml water p, i, angeschl anmt WAD darch Auffiillen with water p. i. on 1000 ml drawn. The l_.6sung is abgefiallt and heat-sterilized in ampuls. RK 397,465 B with ie142 ago tell ang a Lgsung de Di-Sodium salt of the Ytterbium-III-Komplexe8 of the Diethylentriamin l) entae ig303,5 g (= 500 mMol) in example 6 aufgeftihrten S of alzes in 500 ml Wasserp.i. angeschlammt and through Auffttllen with water p. i. on 1000 ml gel pc. the L0sung is heat-sterilized in ampuls abgef'ttllt WAD. Betel 43 Hers'tellung it a Lgsun of the Tetm N Mgths, 1 glueaminc alzes de Condominium III KqmNexe of the E vlen niMl tetrakis (methanvhosvhons ure 137.1 g (= 100 mMol) in example 12 aufgef Jhrten of salt become in 500 ml water p. i. angeschl nmt and after Mugabe yon 0.8 g Tromethamin by Auff illen with washer p. i. on 1000 ml gelGst. The L0sung is abgefiillt and heat-sterilized in ampuls. With iel 44 Herstellun einerLGsun the Gadolinium-III-K0mplexes N' (2-Hv rqxvethvl) of the ethvlendiamin n, N, N' lrie igsure 1.9 g (= 6.7 mMol) N' (2-l-Iydroxyethyl) ethylendiamin n, N, N' tries industrial union ure and 1.2 g (-- 3.35 mol) gadolinium iii-oxide water p becomes in 6 ml. i. inter I rwiirmen gel Sst. The I sung ampulliert WAD is heat-sterilized. Beisoie145 Herstellun of a L6sung vgm DIN trium alz d¢s Mangan-II-Kqmplexe8 Iran - l, 2-Cv¢lohexvlendiamintetraessi sgure 44.3 g (= 100 mMol) in with iel 9 of angeftihrten salt become under nitrogen protection in 60 ml water p, i. angeschlammt and by Aufftillen mk water p. i. on 100 ml in l sung gebmcht. The l sung is hitzesteO_lisiert ampulliert WAD. Beispie146 I-Ier tellung einerL0$ung of desNalriumsalzes desGadolinium IH complex of the 1.4.8.11 - Tetra z eyelqtctrade¢.anN, N', N " ¢N'"4etraessig ure 552.6 g (-- 1 mol) of the salt specified in example 11 become in water p. i. to 1000 ml gelGst. The l stmg is abgefiillt and heat-sterilized in bottles. With ie147 tellung einerLGsun K vqm Di-sodium salt of the Wismm REAR complex of the Diethvlentriamin Dentaessi Nure 23.4 g (= 50 mMol) bismuth iii-oxide become in 50 ml water p ago. i. suspends. After Mugabe yon Diethylentriamin pentaessigsgure and 4.0 g (= 50 mMol) tznatron one heats 39.3 g up (= 11313 mMol) up to the clear L6sung to the RGckfluB. aufRaumtgmpemtur the abgekUhlteL0sung is ronneutralisiert by Mugabe yon 4.0 g tzna and with water p. i. on 100 ml aufgefttllL L sung is ampulliert and rilisiert hitzesl. Beis ie148 I-Icr teUmag einerL isun g vgm Di-sodium salt of the samarium III Kgmplexe Diethylentriamin pent, 3g igN a58,5 g (= 100 mMol) of the salt aufgeftihrten in example 6 becomes in 65 ml water p. i. mould Erw - men gelGst. One ffillt with water p. i. anf 100 ml total volumes up, ampulliert and heat-sterilizes. Beisoiel 49 H¢r t llong minor LQ ng vqm Di-N-MethTlglucaminsalz of the gadolinium IlI KomDlexes of the 13.23-Dioxo15.18.21-1ris (carboxvmethvl) - 12.15.18.21 .24-t entaazaoentatriacontandisfiure 130.4 g (= 100 mMol) in example 2 aufgefiihrten Saizes become in 250 ml water p. i. angeschl tmmt and tinter Erwarmen gelt sL one ftillt with water p. i. on 500 ml up, ftHlt dieL6sung in ampuls RK) and heat-sterilizes. With iel Herst llung a Lssung of the Di-N-Methylghaeaminsalz of the manganese II Kqmplexes of the Ethglen tiamintetraessi 3.68 g (= 5 mMol) in example of the substance described ate 9 become in 70 ml water p. i. gel-eaten and the l sung with 0,4 g sodium chloride shifts. Anschliegend becomes on 100 ml with water p. i. aufgefGllt WAD the l sung by a Sterilfdter in ampuls abgeftillt. The IA sung is with 280 mOsm. blood isotone. RKs 397,465 B with iel 1 ellung liner L0$0ng vgm Di-sodium salt de 0adolinium-III-Kgmplexe 0er Dig hyl nlrinilril oenta (methanohosohonsaure) 38.57 g (= 50 mMol) animal in Beispie112 besehriebenen ago substance become in 50 ml water p. i. angesehl tmmt. One sets dutch yon tznatron powders to Mugabe to pH 7.2 a WAD fiillt with water p. i. on 100 ml up. The-lot-likes ampulliert WAD is heat-sterilized. Beisoiel 52 Hgrstell in einerLOsun gvom Td-Natfiumsalz of the Mangan4I-Komploxes of the Dielhylen iomin l nlao i ure 39.3 g (= 100 mMol) Diethylealriamin pentaessigsaure are suspended inter $ tickstoffin 100 ml water p.i. and with 11,5 g manganese II earbonat shifted. One heated up on 95 °Cund admits drop by drop 300 ml 1N-Natronlauge. The neutral L0sung is abgefiillt sterilely filtered WAD in ampuls. With iel 53 Zusammensetzun of a powder to the Herstellun of a suspension 4.000 g 3.895 g 0.100 g 0.005 g gadolinium iii-complex of the Diethylentdamin pentaessigsaure (water content 8.0%) saccharose Polyoxyethylenpolyoxypropylen polymere Ammastoffe 8.000 g Beis0ie154 Hgrgtellung of a LOsun of the gadolinium III Komolexes of the Koniu RK Diethvlentrlamin oentaessi the ure with human serum albumin to 20 ml a L0sung of 3 mg of the protein in 0,05 molecular Natriumbiearbonatpuffer (pH 7 - 8) become mg 1,5-Bis (2,6-dioxomorpholino) - 3-azapentan-3-essig ure admitted. One lfiBt 30 minutes with Raumtempemtur riihren and dialysiert anschlielMnd against 0.3 molecular Natriumphosphatpaffer. Then one sett mg gadolinium iii-acetate zti WAD cleans darch gel chromatography at a Sephadex G25-S iule. The received parliamentary group is filtdert sterll and abgefiillt in Multivlals. By Oefriertrocknung a lagerfahiges Trockenpraparat will receive. In similar way receipt one with Immunglobulin the L0sung of the entspreehenden complex konjugates. Beisoie155 Her$ [¢llung liner L0 ung the gadolinium iii-complex of the Konj0gat of the Diethylenlri0min-oentaessigs ure (DTPA) with monoclonal Antik6mer Zn 20 lal a L6snng yon 0.3 mg monoclonal Antikfrper in 0,05 molecular Natriumbicarbonatpuffer (pFI 7 - 8) 1 gnaw a mixed DTPA anhydride (Isobutylchloroforrniat receive e.g. to the DTPA urid) admitted and 30 minutes geriihrt at ambient temperature. One dialysiert against 0,3 molecular Nalriumphosphatpaffer and shifts the received AntikOrpeffraktion with 2 mg of the gadolinium iii-complex of the Ethylendiamintetraessigsiiure (EDTA). After cleaning dutch gel chromatography fibre Sephadex G25 is abgef'dlt and freezingdried the sterilf'dtrierte L6sung in Mnltivials. Using the mixed anhydride of the trans l, 2-Diaminocyclohexan-tetraessig ure (CDTA) one ertfftlt in similar way a L6sung of the entspreehenden gadolinium III Complexes of the CDTA antibody. Under the-manganese-ii-complex derEthylendiamin Te turn-likes igsiiureerl t one similar to the manganese ii-complexes of the Antik0rper coupled with DTPA or CDTA. Beisoiel 56 Herstellunu of a LOsunu of the gadolinium III Komolexes of the KoniIJg ll 0¢r 1-Phenvl-¢thylenOi min lcWd¢$$igs ure mi [Imm0ngl01imlin sew in the J. Meal. Chem. 1974, VOL. One lfiBt tiber night with 14 °C rfihren (pH 8.1) nnd dialysiert anschliel] final against 03 molecular Natriumzitratl6sung. After Abschinl of dialysis the I..6sung of the Konjugats becomes mk (3 a " berschu8 yon gadolinium III chlofid transferred and ultrafiltriert to the Enffemung yon ions. To Absehliel] end the stedlfiltrierte L0sung in Muldvials abgefiillt and one gefriergetmeknet. RKs 397,465 B BeisDiel 57 Herstellun of a colloidal Digl r i0n of tines Mn-CDTA-LiDid-K0niu aIS 0.1 mMol Distearoylphosphatidylethanolamin and 0.1 mMol until anhydride of the trans l, 2-Diaminoeyelohexantetraessigsaure are geriihrt in 50 ml water 24 hours at ambient temperature. One admits 0.1 mMol manganese IIcarbonat and riihrt emeut to 6 Stmaden at ambient temperature. After cleaning more tiber a Sephadex G50-Saule wlrd the sterile-filtered password in Multivials abgefiillt WAD freezingdried. Similar to l a colloidal dispersion of the gadolinium DTPA Lipid Konjugats gt itself received with gadolinium iii-oxide. BeisDiel 58 production v0n mi gadolinium DTPA! 3eladenen Lipos0men Naeh in Proe. Natl. Aead. Sci. U.S.A. 75, 4194 descriptive approach a Lipid Gemiseh is manufactured to the Mol% egg-Phosphatidyleholin WAD 25 Mol% Cholesterol as Trockensubstanz. Of it become 500 gnaw in 30 ml Diethylether gol6st WAD in the ultrasonic bath drop by drop with 3 ml 0.1 a molecular password of the DIN Methylglucaminsalzes of the gadolinium iii-complex Diethylentriamin penta sig ium in Wm of the r p. i. shifted, well h vollst indiger Mugabe that lot-likes continues one the UltmbeschaUung after 10 minutes and restricts then in the Rotavapor. The gel-like RiJckstand is suspondiert in 0,125 of molecular sodium chloride draw and released with 0 °C repetitive dutch centrifugation (20000 g/20 Minnten) yon not-encased contrast central portions. AbschlieBend warden in such a way received Liposomen in the Multivial gefriergetrocknet_ the application effolgt Al colloidal dispersion in 0,9 of weight-per cent common salt draw.