CN101223148A

CN101223148A - Perfluoroalkyl-containing complexes, process for their production as well as their use

Info

Publication number: CN101223148A
Application number: CNA2006800258905A
Authority: CN
Inventors: H·席尔默; H-J·魏因曼; J·普拉策克; L·措恩; B·米塞尔维茨; J·梅丁; H·施米特-维利希; T·布伦比
Original assignee: Schering AG; Epix Pharmaceuticals Inc
Current assignee: Bayer Pharma AG
Priority date: 2005-07-15
Filing date: 2006-07-11
Publication date: 2008-07-16
Also published as: TW200706538A; GT200600313A; DE102005033902B3; TNSN08016A1; AR054865A1; DOP2006000167A; PE20070376A1; CR9645A; KR20080043762A; CA2615443A1; ECSP088100A; WO2007009638A2; BRPI0613407A2; ZA200801523B; EP1904463A2; WO2007009638A3; NO20080813L; UY29664A1; IL187926A0; RU2008105356A

Abstract

The invention relates to objects which are characterised in the claims, that is, metal complexes containing perfluoroalky, comprising radicals of general formula I containing nitrogen, to a method for the production and use thereof in the NMR field and x-ray diagnosis, radiodiagnosis and radiotherapy, in addition to lymphography in the MRT field and for blood pool imaging.

Description

Perfluoroalkyl-containing complexes, its preparation method and application thereof

The present invention relates to the theme of characterization in the claim, be general formula I have a nitrogen-containing group contain the perfluoroalkyl metal complex, its preparation method and in NMR and x X-ray diagnosis X, radiodiagnosis and radiotherapy and the application in MRT lymphography and blood pool imaging.To contain the perfluoroalkyl metal complex be used for nuclear spin resonance tomography (MRT) to be used for showing (visualize) thus different physiology and physiopathology structure and the diagnostic message of improving are disease location and degree, select and the success of monitoring therapeutic interest and be used for prevention.

Compound of the present invention is suitable for lymphography extremely especially, is used for diagnosing tumor and is used for infraction and downright bad video picture.

In the nucleus magnetic resonance field, the more known fluorochemicals that can in the video picture field, use.Yet, in most of the cases, only propose that these compounds are used for fluoro-19 video pictures and only are suitable for this application.For example, at United States Patent (USP) 4,639,364 (Mallinckrodt), DE 4203254 (Max-Planck-Gesellschaft), WO 93/07907 (Mallinckrodt), US 4,586,511 (Children ' s Hospital Medical Center), EP 307863 (Air Products), US4,588, these compounds are disclosed among 279 (University of Cincinnati, Children ' s Hospital ResearchFoundation) and the WO 94/22368 (Molecular Biosystems).

At US 5,362,478 (VIVORX), United States Patent (USP) 4,586,511, among DE 4008179 (Schering), WO 94/05335 and WO 94/22368 (being the molecular biosciences system), EP 292306 (TERUMO Kabushiki Kaisha), EP 628 316 (TERUMO KabushikiKaisha) and the DE 4317588 (Schering) other fluorochemicals that can be used for video picture is disclosed.

Though in the compound that contains element fluorine and iodine, do not interact between the dinuclear, interact but intensive takes place in the compound that contains fluorine and paramagnetic center (group, metal ion), and the interaction of described intensive is represented with the shortening in the relaxation time of fluorine atom nuclear.The degree of this effect depends on the unpaired electron number (Gd of metal ion ³⁺＞Mn ²⁺＞Fe ³⁺＞Cu ²⁺) and paramagnetic ion and ¹⁹Moving between the F atom.

The unpaired electron of metal ion exists many more and metal ion is near more from fluorine, and then the shortening in the relaxation time of fluorine atom nuclear is big more.

It is obvious having in the odd number spin population purpose nuclear as the shortening in relaxation time of the function of the spacing of paramagnetic ion at all, therefore under the situation of proton too, so gadolinium compound is widely used as contrast medium (Magnevist in the nuclear spin laminography video picture ^, Prohance ^, Omniscan ^And Dotarem ^).

Yet, ¹The H-MR video picture ( ¹H-MRI) in, measure the relaxation time T that proton promptly is mainly water proton ¹Or T ², rather than the relaxation time of fluorine atom nuclear, and be used for video picture.Quantitative measurment for the shortening in relaxation time is relaxivity [L/mmol.s].For shortening the relaxation time, successfully used the complex compound of paramagnetic ion.In following table, show the relaxivity of several commercial formulation:

	T in water ¹Relaxation property [L/mmols, 39 ℃, 0.47T]	T in blood plasma ¹Relaxation property [L/mmols, 39 ℃, 0.47T]
	T in water ¹Relaxation property [L/mmols, 39 ℃, 0.47T]		MAGNEVIST ^	3.8	4.8
DOTAREM ^	3.5	4.3	MAGNEVIST ^	3.8	4.8
DOTAREM ^	3.5	4.3	OMNISCAN ^	3.8	4.4
PRO HANCE ^	3.7	4.9	OMNISCAN ^	3.8	4.4

In these compounds, only between proton and gadolinium ion, interact.Thereby in water, observe about 4[L/mmols for these contrast medium] relaxivity.

Therefore, be used for the fluorine cpd (wherein using the relaxation time of the shortening of fluorine atom nuclear) of fluoro-19 video pictures and not fluorochemicals (wherein measuring the relaxation time of the proton of water) all be successfully used to the MR video picture.

Introduce in the paramagnetic contrast agent will containing the perfluorocarbon group, under the situation of the known character that is only applicable to fluorine video picture compound and the properties of combination of the compound that is used for the proton video picture, the relaxivity relevant with the proton of water be increase fast also before being about to.With as above the table in to some commerical prods described 3.5 and 3.8[L/mmols] between value compare, now reached 10-50[L/mmols] value.

From DE 196 03 033.1, WO 99/01161, DE 19914101, DE 10040381 and the DE 10040858 known perfluoroalkyl metal complexs that contain.Yet for all applications, because in most of the cases consistency is not enough, so these compounds use unsatisfactorily.Therefore, still need not only to have excellent video picture characteristic simultaneously in the Noninvasive that obtains diagnostic method but also MRT contrast medium with excellent consistency.For example, if will diagnose the tumour that comprises satellite shape metastasis and therefore will obtain the distribution of contrast medium in whole machine body, then this is important.

Malignant tumour shifts at bunch shape of regional nodes, wherein can relate to several lymphoglandula positions.Therefore, in all suffer from about 50-69% of patient of malignant tumours, find nodus lymphoideus transferring rate (Elke, Lymphographie[Lymphography], at Frommhold, Stender, Thurn (volume), Radiologische Diagnostik in Klinik und Praxis[RadiologicalDiagnosis in Clinical Studies and in Practice], the IV volume, Thieme VerlagStuttgart, the 7th edition, 434-496 is in 1984).About the treatment and the prognosis of malignant disease, the diagnosis of nodus lymphoideus transferring rate invasion and attack is very important.With the still not enough lymphatic metastasis that detects malignant tumour of modern developing method (CT, US and MRI),, only there is the size of lymphoglandula to can be used as Case definition because in most of the cases.Therefore, little metastasis in the non-enlarged lymph node (＜2cm) can not distinguish (people such as Steinkamp with the lymph node hyperplasia of no pernicious invasion and attack mutually, Sonographie und Kernspintomographie:Differentialdiagnostik yonreaktiver Lymphknoten-vergr  β erung und Lymphknotenmetastasen amHals[Sonography and Nuclear Spin Tomography:DifferentialDiagnosis of Reactive Lymph Node Enlargement and Lymph NodeMetastases on the Neck], Radiol.Diagn.33:158,1992).

To expect, and when using particular contrast agent, can distinguish the lymphoglandula and the hyperplasia lymphoglandula of transitivity invasion and attack.

Known direct x ray lymphography (oil contrast media suspension is injected in the preliminary lymphatic vessel) is for showing the intrusion method of a little lymphatic drainage position, and it only uses under few cases.

The fluorescent mark dextran also tentatively be used for experimentation on animals with can with they through between observe lymphatic drainage after the matter administration.Between behind matter/intradermal administration, all are generally used for showing that the marker of lymphatic vessel and lymphoglandula has the total fact, be that they are material or the big polymkeric substance (referring to above WO90/14846) with particle properties (" particle ", for example emulsion and how Mi Jingti suspension).Yet, proved previous formulations since part of its difference and whole body consistency with and little lymphatic vessel passage, cause diagnosis efficiency not enough, therefore still be not applicable to indirect lymphography best.

Owing to show that lymphoglandula is most important for the invasion and attack of early detection cancer patients transitivity, therefore be starved of with extraordinary consistency and be feature, be used to diagnose the lymph particular contrast agent preparation of lymphoid respective change.According to the present invention, lymphsystem comprises lymphoglandula and lymphatic vessel.Therefore, material of the present invention is suitable for the diagnosis that lymphsystem changes, and preferably is suitable for the diagnosis that lymphoglandula and/or lymphatic vessel change, the diagnosis that is particularly suitable for shifting in the lymphoglandula.

As the lymph concentration of diagnosing several relevant lymph positions is consistent as far as possible the same, expects that contrast concentration and high stability are high as far as possible.Should reduce burden by draining contrast medium fast and fully to whole machine body.For the radioactivity operation, if possible, after giving contrast medium, begin fast in several hours as early as possible.Good consistency is essential.

At last but importantly, expect to have obtainable lymph particular contrast agent, it makes and show primary tumo(u)r and possible nodus lymphoideus transferring rate kitchen range between diagnostic period.

Another important medical field is for detecting, locate and monitoring necrosis or infraction.Therefore, myocardial infarction and nonstatic process, but the dynamic process that in long-time (several weeks are to the several months), develops.This disease progression process is about three phases, and they are not separately strict but eclipsed each other.Fs: the generation of myocardial infarction, comprise 24 hours after the infraction, wherein destroy as shockwave (wavefront phenomenon), under endocardium, marching to cardiac muscle.Subordinate phase: had infraction, comprised the area stabilization, wherein formed (fibrosis) and take place with the agglutination fiber.Phase III: the infraction healing, it begins after all destroyed tissues are replaced by fibrous scar.During this period, reconstruct widely takes place.

Up to now, can diagnose out the accurate and reliable method of the current generation of the myocardial infarction among the patient of survival still not know.Be to estimate myocardial infarction, the part of knowing the tissue of definite loss in infraction have much and loss occurrence most important wherein because the treatment type depends on this knowledge.

Not only in cardiac muscle but also in other tissue, particularly in brain, all block.

Though infraction can heal to a certain extent,, only can prevent under the situation of the tissue die of local finite or alleviate harmful result at least the body rest part in necrosis.Necrosis can be in many ways: take place by wound, pharmaceutical chemicals, anoxic or by radiation.As under the situation of infraction, understanding downright bad scope and type is important for further medical treatment.

Therefore, using contrast medium to test with the location of improving infraction and necrosis in such as the noninvasive method of scintigraphy or nuclear spin laminography video picture carries out more already.In the literature, the test of using porphyrin to be used for downright bad video picture occupies a large amount of lengths.Yet the result of acquisition is contradictory.In addition, porphyrin is tending towards depositing in skin, and this causes photosensitive.

The non-contrast medium derived from the porphyrin skeleton that is used for necrosis and infraction video picture has description at DE19744003 (Schering AG), DE 19744004 (Schering AG) and WO99/17809 (EPIX).Yet up to now, still not having can be satisfactorily with acting on contrast medium in infraction and the downright bad video picture and the compound that has superior compatibility simultaneously.

Exist same problem in can be used for diagnosing the compound field of thrombus or arteriosclerosis plaque: not having can be satisfactorily as showing thrombus or the contrast medium of arteriosclerosis plaque and the compound that has superior compatibility simultaneously.

Therefore, the objective of the invention is to prepare obtainable contrast medium, described contrast medium has the excellent video picture characteristic as the MRT contrast medium on the one hand, and be specially adapted to tumour and downright bad video picture and/or lymphography and/or blood pool imaging and/or be used to show thrombus or arteriosclerosis plaque, and be feature with the superior compatibility simultaneously.

Purpose of the present invention realizes by the perfluoroalkyl-containing complexes of the nitrogenous connection based structures of having of general formula I,

Wherein

R represents:

By the monose or the oligosaccharides group of 1-OH connection,

Q has the implication that is selected from following group in the case:

δ-CO-(CH ₂) _n″-ε

δ-NH-(CH ₂) _n″-ε

δ-(CH ₂) _m-ε

Wherein:

N " be 1 to 5 integer, and

M is 1 to 6 integer, and

Wherein δ represents and is connected the connection site that basic L connects, and ε represents the connection site that is connected with radicals R;

Or

R has one of following implication, and then Q has the implication of direct key: R and is selected from following polar group

The complex compound K of general formula I I to V, wherein R ¹Herein for hydrogen atom or ordination number are 20-29,31-33,37-39,42-44,49 or the metal ion Equivalent of 57-83, and radicals R ², R ³, R ⁴, U and U ¹Have implication shown below,

Or

Have the passing through of 1-30 C atom-CO-,-NR ⁷-or directly key be connected to the carbochain that connects basic L,

It can be straight or branched, saturated or undersaturated, and

Its

Optional be interrupted by 1-10 Sauerstoffatom, 1-5-NHCO group, 1-5-CONH group, a 1-2 sulphur atom, 1-5-NH group or 1-2 phenylene, its can choose wantonly by 1-2-OH group, 1-2 individual-NH2 group, 1-2 be individual-COOH group or 1-2 be individual-SO ₃The H group replaces, and its

Optional by 1-10-OH group, 1-5-COOH group, 1-2-SO ₃H group, 1-5-NH ₂A group or 1-5 C ₁-C ₄-alkoxyl group replaces,

R wherein ⁷Be H or C ₁-C ₄Alkyl,

R _fFor having formula-C _nF _2nPerfluorination straight chain or the branched chain of E, wherein E represents terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n represents digital 4-30,

K represents the metal complex of general formula I I,

Wherein

R ¹For hydrogen atom or ordination number are 21-29,31-33,37-39,42-44,49 or the metal ion Equivalent of 57-83,

Condition is at least two R ¹Expression metal ion Equivalent,

R ²With R ³Represent hydrogen, C independently of each other ₁-C ₇-alkyl, benzyl, phenyl ,-CH ₂OH or-CH ₂OCH ₃, and

U represents optional by one or more Sauerstoffatoms, 1 to 3-NHCO group or 1 to 3-CONH group interruption and/or by 1 to 3-(CH ₂) _0-5The COOH group replaces-C ₆H ₄-O-CH ₂-ω-,-(CH ₂) _1-5-ω, phenylene ,-CH ₂-NHCO-CH ₂-CH (CH ₂COOH)-C ₆H ₄-ω ,-C ₆H ₄-(OCH ₂CH ₂) _0-1-N (CH ₂COOH)-CH ₂-ω or C ₁-C ₁₂-alkylidene group or-(CH ₂) _7-12-C ₆H ₄-O group, wherein ω represents and-connection site that CO-is connected;

Or the metal complex of general formula III

R wherein ¹Has above-mentioned implication, R ⁴Expression hydrogen or at R ¹Mentioned metal ion Equivalent, and U down ¹Expression-C ₆H ₄-O-CH ₂-ω-or group-(CH ₂) _p-, wherein ω be with-connection site and p that CO-is connected ¹It is the integer between 1 and 4;

Or the metal complex of general formula I V

R wherein ¹With R ²Has above-mentioned implication;

Or the metal complex of general formula VA or VB

R wherein ¹Has above-mentioned implication;

Or the metal complex of general formula VI

R wherein ¹Has above-mentioned implication;

Or the metal complex of general formula VII

R wherein ¹And U ¹Have above-mentioned implication, wherein ω is and-connection site that CO-is connected;

Or the metal complex of general formula VIII

R wherein ¹Has above-mentioned implication;

And U ²Represent straight or branched, saturated or undersaturated C ₁-C ₂₀Alkylidene group, optional imino-, phenylene, inferior phenoxy group, inferior phenylimino, acid amides, hydrazides, carbonyl, ester group, oxygen, sulphur and/or the nitrogen-atoms and optional of containing of described alkylidene group by hydroxyl, sulfydryl, oxo, sulfo-, carboxyl, carboxyalkyl, ester group and/or amino the replacement

And choose the free acid group that in group K, exists wantonly and can choose wantonly as the salt of organic and/or mineral alkali or amino acid or amino acid amide and exist,

And L represents to be selected from following group IXa) to IXc) group:

Wherein n ' and m ' represent the integer between 0 and 4 independently of each other, and m '+n ' 〉=1; Preferably, m '+n ' equals 1,2 or 3, and

R ⁸With R ^{8 '}Be independently of each other-H or-OH, m '+n '＞1 wherein, each group-(CR ⁸R ^{8 '})-can be inequality, and

W be direct key ,-O-maybe can choose the phenylene that is replaced by 1 to 4 hydroxyl wantonly,

And q ' is 1,2,3 or 4;

Wherein α is the connection site that L is connected with complex compound K, and β is the connection that L is connected with group Q

The site, and γ represents the connection site that L is connected with radicals X;

And

The group of X expression (X);

ρ—Y—(CH ₂) _s—(G) _t—(CH ₂) _s’—ζ

(X)，

Wherein Y is direct key, group-CO-or group NR ⁶,

R wherein ⁶Expression-H or straight or branched, saturated or undersaturated C ₁-C ₁₅Carbochain,

Described carbochain can be by 1-4 O atom, 1-3-NHCO group, 1-3-CONH group, 1-2-SO ₂Group, a 1-2 sulphur atom, 1-3-NH group or 1-2 phenylene interruption,

It can be chosen wantonly by 1-2-OH group, 1-2-NH2 group, 1-2-COOH group or 1-2-SO ₃The H group replaces,

And described carbochain optional by 1-10 OH group, 1-5-COOH group, 1-2 individual-SO ₃H group, 1-5-NH ₂A group or 1-5 C ₁-C ₄-alkoxyl group replaces;

And G is-O-or-SO ₂-,

S and s ' they are 1 or 2 independently of each other, and t is 0 or 1, and

ρ represents the connection site that X is connected with L, and ζ represents X and R _fThe connection site that connects.

In preferred embodiments, R ⁶Be the H or the C that can be interrupted by 1-3 O atom and can be replaced by 1-4-OH group ₁-C ₆-alkyl.

In particularly preferred embodiments, R ⁶Be C ₁-C ₄Alkyl.

In preferred embodiments, G is group-O-.

In particularly preferred embodiments, t=0.

In preferred embodiments, W is direct key.

In preferred embodiments, by-CO-,-NR ⁷-or directly key be connected to the radicals R that connects basic L be have 1-30 C atom be interrupted by 1 to 10 Sauerstoffatom and/or by the carbochain of 1-10 OH group replacement.

In particularly preferred embodiments, R for by-CO-,-NR ⁷-or directly key be connected to L, be interrupted by 1 to 6 Sauerstoffatom and/or by the C of 1-6 OH group replacement ₁-C ₁₂Carbochain.

If be intended to compound of the present invention is used for NMR diagnosis, then the metal ion of ensemble is necessary for paramagnetic.These particularly ordination number be 21-29,42,44 and the divalence and the trivalent ion of the element of 58-70.Suitable ion for example is chromium (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III) and ytterbium (III) ion.Gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), iron (III) and manganese (II) ion are preferred especially because of their strong magnetic moment.

For the application of compound of the present invention in nuclear medicine (radiodiagnosis and radiotherapy), metal ion is necessary for radioactive.For example, ordination number is 27,29, the radio isotope of 31-33,37-39,43,49,62,64,70,75 and 77 elements is fit to.Preferred technetium, gallium, indium, rhenium and yttrium.

If be intended to compound of the present invention is used for the x X-ray diagnosis X, then metal ion preferably from than the element of high atomic number to realize enough absorptions of x ray.Find, for this purpose, contain have ordination number be 25,26 and 39 and the diagnostic reagent of the compatible complex salts of the physiology of the metal ion of the element of 57-83 be fit to.

Manganese (II), iron (II), iron (III), praseodymium (III), neodymium (III), samarium (III), gadolinium (III), ytterbium (III)) or bismuth (III) ion preferred, particularly dysprosium (III) ion and yttrium (III) ion are preferred.

R ¹In the optional acid hydrogen atom that exists, i.e. the hydrogen atom that is not replaced by central ion can be chosen wantonly by positively charged ion inorganic and/or organic bases or amino acid or amino acid amide is all or part of and substitutes.

Suitable inorganic cation for example is lithium ion, potassium ion, calcium ion, particularly sodium ion.Suitable organic bases positively charged ion is primary amine, secondary amine or tertiary amine, such as thanomin, diethanolamine, morpholine, glycosamine, N, and the positively charged ion of N-dimethyl glycosamine, the particularly positively charged ion of N-methyl grape amine.Suitable amino acid positively charged ion for example is the positively charged ion of the acid amides of the positively charged ion of Methionin, arginine and ornithine and other acidity or neutral amino acids.

The compound of particularly preferred general formula I is the compound with macrocylc compound K of general formula I I.

Group U among the metal complex K is preferably-CH ₂-or C ₆H ₄-O-CH ₂-ω, wherein ω represents and-connection site that CO-is connected.

In preferred embodiments, U ²Be C ₁-C ₆Alkylidene chain, it is chosen wantonly by 1 to 2-NHCO group and/or 1 to 2 O atom and is interrupted and can be replaced by 1 to 3-OH group.

Group U among the metal complex K ²Preferably be in particular:

-have 1 to 6 a C atom, the particularly straight-chain alkyl-sub-of 2,3 or 4 C atoms, or

-having 1 to 6 C atom, the particularly straight-chain alkyl-sub-of 2,3 or 4 C atoms, described alkylidene group is interrupted by 1 O atom, or

-having 1 to 6 C atom, the particularly straight-chain alkyl-sub-of 2,3 or 4 C atoms, described alkylidene group contains-the NHCO group.

In particularly preferred embodiments, U ²Be ethylidene.

Alkyl R in the macrocylc compound of general formula I I ²And R ³Can be straight or branched.For example, can mention methyl, ethyl, propyl group, sec.-propyl, normal-butyl, 1-methyl-propyl, 2-methyl-propyl, n-pentyl, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl and 1, the 2-dimethyl propyl.R ²With R ³Be preferably hydrogen or C independently of each other ₁-C ₄Alkyl.

In particularly preferred embodiments, R ²Expression methyl, and R ³Expression hydrogen.

Benzyl in the macrocylc compound of general formula I I or phenyl R ²Or R ³Also can in ring, be substituted.

In another embodiment preferred of the present invention, R is the monose group with 5 or 6 C atoms, be preferably glucose, seminose, semi-lactosi, ribose, pectinose or wood sugar or their desoxy sugar, such as 6-deoxy-galactose (trehalose) or 6-deoxymannose (rhamnosyl) or their all alkyl derivative.Be preferably glucose, seminose and semi-lactosi especially, be in particular seminose.

In another embodiment preferred of the present invention, R is selected from one of following group:

-C(O)CH ₂O[(CH ₂) ₂O] _pR′

-C(O)CH ₂OCH[CH ₂OCH(CH ₂OR′) ₂] ₂

-C(O)CH ₂OCH ₂CH[CH ₂OCH(CH ₂OR′) ₂] ₂

-R″N[(CH ₂) ₂O] _pR′

-N{[(CH ₂) ₂O] _pR′} ₂

-R″NCH ₂CH(OH)CH ₂OH

-N[CH ₂CH(OH)CH ₂OH] ₂

-R″NCH(CH ₂OH)CH(OH)CH ₂OH

-N[CH(CH ₂OH)CH(OH)CH ₂OH] ₂

-R″NCH[CH ₂OCH(CH ₂OR′) ₂] ₂

-R″NCH ₂CH[CH ₂OCH(CH ₂OR′) ₂] ₂

-R″NCH ₂CH ₂OCH[CH ₂OCH(CH ₂OR′) ₂] ₂

-R″NCH ₂CH ₂OCH ₂CH[CH ₂OCH(CH ₂OR′) ₂] ₂

-N{CH[CH ₂OCH(CH ₂OR′) ₂] ₂} ₂

-N(CH ₂CH[CH ₂OCH(CH ₂OR′) ₂] ₂} ₂

-R″NCH ₂CH(OH)CH(OH)CH(OH)CH(OH)CH ₂OH

-N[CH ₂CH(OH)CH(OH)CH(OH)CH(OH)CH ₂OH] ₂

Reach the complex compound that Q has the formula (II) of direct key implication,

R wherein ¹, R ², R ³And U such as above to formula (II) definition,

P is 1,2,3,4,5,6,7,8 or 9,

R ¹Be H or CH ₃, and R " is H or C ₁-C ₄-alkyl.

P is preferably 1,2,3 or 4.

Polar group shown here is commercially available product or prepares according to method described in the document.

People such as Cassel, Eur.J.Org.Chem., 2001,5,875-896

People such as Whitessides, JACS, 1994,5057-5062

People such as Voegtle, Liebigs Ann.Chem., 1980,858-862

People such as Liu, Chem.Commun., 2002,594

People such as Mitchell, Heterocyclic Chem., 1984,697-699

People such as Bartsch, J.Org.Chem., 1984,4076-4078

People such as Keana, J.Org.Chem., 1983,2647-2654

In particularly preferred embodiments, R is connected to formula-C (O) CH of L for warp-CO- ₂O[(CH ₂) ₂O] _PThe group of R '.

When p and R ' had above-mentioned implication, R ' was preferably group CH especially ₃

In another embodiment preferred, Q has the implication that is selected from following group:

δ-CO-(CH ₂) _n″-ε

Wherein:

N " be 1 to 5 integer, and

L has the implication of formula IXa or IXb group simultaneously.

δ-NH-(CH ₂) _n″-ε

Wherein:

N " be 1 to 5 integer, and

L has the implication of group IXc simultaneously.

In the compound of general formula I of the present invention, in addition, preferred R wherein _fFor-C _nF _2n+1Compound; Be formula-C _nF _2nE among the E is a fluorine atom.N preferably represents digital 4-15.Very particularly preferably be group-C ₄F ₉,-C ₆F ₁₃,-C ₈F ₁₇,-C ₁₂F ₂₅And-C ₁₄F ₂₉And the group of the compound of mentioning among the embodiment.

In the preferred embodiments of the invention, the nitrogen-containing group L of the expression in the general formula I " skeleton " is amino acid group (Vc).

In another embodiment preferred, nitrogen-containing group L expression (IXb) or diamine groups (IXa) in the general formula I.

General formula I have nitrogenous connection based structures contain the perfluoroalkyl metal complex in mode as known in the art by being prepared as follows,

Wherein K has the implication of the metal complex of general formula I I to IV, and L, Q, X, R and R _fHave above-mentioned implication,

By making the carboxylic acid of general formula I Ia

R wherein ⁵For ordination number is 21-29,31-33,37-39,42-44,49 or 57-83

Metal ion Equivalent or carboxyl-protecting group, and R ², R ³Reach U and have above-mentioned implication, or the carboxylic acid of general formula III a

R wherein ⁴, R ⁵And U ¹Have above-mentioned implication,

Or the carboxylic acid of general formula I Va

R wherein ⁵With R ²Have above-mentioned implication,

Or the carboxylic acid of general formula Va or Vb

R wherein ⁵Have above-mentioned implication,

Or the carboxylic acid of general formula VIa

R wherein ⁵Have above-mentioned implication,

Or the carboxylic acid of general formula VIIa,

R wherein ⁵With U ¹Have above-mentioned implication,

R wherein ⁵With U ²Have above-mentioned implication,

With the form of optional activation and the amine of general formula X I

Wherein L, R, R _f, Q and X have above-mentioned implication,

Carry out linked reaction, and choose the metal complex of the optional protecting group that exists of cracking subsequently wantonly with the formation general formula I,

Perhaps

If R ⁵Implication with protecting group; in later step, be 21-29,31-33,37-39,42-44,49 or the metal oxide or the reacting metal salt of the element of 57-83 after these protecting groups of cracking then with mode as known in the art and at least a ordination number; if need, the optional acid hydrogen atom that exists is replaced by the positively charged ion of inorganic and/or organic bases, amino acid or amino acid amide then.

This method that is used to prepare the metal complex carboxylic acid amide is known from DE 196 52 386.

Use in the linked reaction and by the metal complex carboxylic acid IIIb of optional carboxyl that contains protected form and/or hydroxyl and at least a with respect to described metal complex carboxylic acid 5 molar equivalents at the most; the mixture that the solubilising material of the amount of preferred 0.5-2 molar equivalent is formed can and separate in the preparation of upstream reaction stage (for example by evaporation; the miscible solution of the aqueous solution of freeze-drying or these components of spraying drying or water or concentrated) by precipitating from this solution with organic solvent; can in DMSO, react with dewatering agent and the coupling auxiliary agent of choosing wantonly then, and can be by the solubilising material is added in the DMSO suspension by the metal complex carboxylic acid; dewatering agent and the optional optional original position of coupling auxiliary agent form.

To remain under 0 to 50 ℃ the temperature pre-treatment (acid activation) 1 to 24 under the preferred room temperature, preferred 3 to 12 hours according to the reaction soln of one of these methods preparations.

Then, incite somebody to action wherein group L, R, R _f, Q and X have the amine of the general formula X I of above-mentioned implication

Under solvent-free situation or with dissolved form for example be dissolved in methyl-sulphoxide, alcohol as methyl alcohol, ethanol, Virahol or its mixture, methane amide, dimethyl formamide, water or as described in the mixture of solvent, be preferably dissolved in methyl-sulphoxide, water or with water blended solvent in and add.For the acid amides coupling, the reaction soln that so obtains is remained on 0 to 70 ℃, under preferred 30 to the 60 ℃ temperature 1 to 48 hour, preferred 8 to 24 hours.

Under the certain situation, having used the amine of its salt form in the proved response is favourable as hydrobromate or hydrochloride for example.For discharging amine, add alkali for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, tripropyl amine, Tributylamine, lithium hydroxide, Quilonum Retard, sodium hydroxide or yellow soda ash.

The protecting group that still exists is chosen in cracking wantonly then.

The separation of reaction product is according to method known to those skilled in the art, and preferably by carrying out with organic solvent deposit, described organic solvent is preferably acetone, 2-butanone, ether, ethyl acetate, methyl tertiary butyl ether, Virahol or its mixture.Other purifying can be undertaken by for example chromatogram, crystallization or ultrafiltration.

As the solubilising material, the salt of an alkali metal salt, alkaline earth salt, trialkyl ammonium salts, tetraalkylammonium salt, urea, N-hydroxyl imide, hydroxyaryl triazole, substituted phenol and heterocyclic amine is fit to.For example, can mention lithium chloride, lithiumbromide, lithium iodide, Sodium Bromide, sodium iodide, the methylsulfonic acid lithium, methanesulfonic sodium, the tosic acid lithium, paratoluenesulfonic acid sodium salt, Potassium Bromide, potassiumiodide, sodium-chlor, magnesium bromide, magnesium chloride, magnesium iodide, tetraethyl ammmonium p toluene sulfonate, the tosic acid tetramethylammonium, the tosic acid pyridine, tosic acid three second ammoniums, 2-morpholino ethyl sulfonic acid, the 4-nitrophenol, 3, the 5-dinitrophenol, 2,4-two chlorophenols, N-maloyl imines, the N-hydroxyphthalimide, urea, tetramethyl-urea, N-Methyl pyrrolidone, methane amide and ring-type urea, wherein above-mentioned the first five kind is for preferred.

Use all reagent well known by persons skilled in the art as dewatering agent.For example, can mention carbodiimide and reagent, such as dicyclohexylcarbodiimide (DCCI), 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDC), benzotriazole-1-oxygen base three (dimethylamino)-phosphonium hexafluorophosphates (benzotriazol-1-yloxytris (dimethylamino)-phosphoniumhexafluorophosphate, BOP) and neighbour-(benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate (HBTU) is preferably DCCI.

For example following proper method is described in the document:

◆ Aktivierung von Carbons  uren.Ubersicht in Houben-Weyl, Methoden der Organischen Chemie[Activation of Carboxylic Acids.Survey in Houben-Weyl, Methods of Organic Chemistry], the XV/2 volume, Georg Thieme Verlag Stuttgart, 1974 (and J.Chem.Research (S) 1996,302).

◆ Aktivierung mit Carbodiimiden[Activation with Carbodiimides] .R.Schwyzer and H.Kappeler, Helv.46:1550 (1963).

◆ people such as E.W ü nsch, the 100th volume: 173 (1967).

◆ Aktivierung mit Carbodiimiden/Hydroxysuccinimid[Activationwith Carbodiimides/Hydroxy Succinimide]: J.Am.Chem.Soc.86:1839 (1964) and J.Org.Chem.53:3583 (1988) .Synthesis 453 (1972).

◆Anhydridmethode，

2-Ethoxy-1-ethoxycarbonyl-1,2-dihydrochinolin[Anhydride Method, 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline]: people such as B.Belleau, J.Am.Chem.Soc., 90:1651 (1986), people such as H.Kunz, Int.J.Pept.Prot.Res., 26:493 (1985) and J.R.Voughn, Am.Soc.73:3547 (1951).

◆Imidazolid-Methode[Imidazolide Method]：B.F.Gisin，R.B.Menifield，D.C.Tosteon，Am.Soc.91：2691(1969)。

◆Surechlorid-Methoden，Thionylchlorid[Acid Chloride Methods，Thionyl Chloride]：Helv.，42：1653(1959)。

◆Oxalylchlorid[Oxalyl Chloride]：J.Org.Chem.，29：843(1964)。

As the optional coupling auxiliary agent that uses, all coupling auxiliary agents well known by persons skilled in the art all are suitable (Houben-Weyl, Methoden der organischen Chemie, XV/2 volume, Georg Thieme-Verlag, Stuttgart, 1974).For example, can mention 4-nitrophenol, N-maloyl imines, I-hydroxybenzotriazole, 1-hydroxyl-7-azepine-benzotriazole, 3,5-dinitrophenol and pentafluranol.Be preferably 4-nitrophenol and N-maloyl imines; This is preferably especially above-mentioned first reagent.

The cracking of protecting group is carried out according to method known to those skilled in the art; for example by hydrolysis, hydrogenolysis, in water-alcohol solution, ester carried out alkaline saponification under 0 ℃ to 50 ℃ the temperature, carrying out acid saponification with mineral acid or carrying out acid saponification [Protective Groups in Organic Synthesis under the help at trifluoroacetic acid under the tertiary butyl ester situation for example with alkali; second edition; T.W.Greene and P.G.M.Wuts; John Wiley and Sons; Inc.New York, 1991], under the situation of benzyl oxide, use hydrogen/palladium/carbon to carry out.

The carboxylic acid of the general formula I Ia to VIIa that uses is as known compound or according to the method preparation of describing among the embodiment, referring to DE 10040381 and DE 10040858.Therefore, from the preparation of the carboxylic acid of DE 196 52386 known general formula I Ia.Prepare described in the carboxylic acid of the general formula VIIIa that uses such as the WO95/17451.

Phenmethyl saccharic acid (perbenzylated sugar acid) excessively as initial substance when R is monose or oligosaccharides can be similar to Lockhoff, Angew.Chem.[AppliedChem.] 1998,110 the 24th phases, the 3634th page of preparation.Therefore, for example prepare 1-O-acetate and carry out: through three chloroethene imido-esters and be BF among the THF through 2 stages by crossing phenmethyl glucose ₃Following and the hydroxyl ethyl acetate reaction of catalysis is used to the NaOH saponification among the MeOH/THF subsequently.

In advantageous method more, described in DE 10040381, crossing the phenmethyl saccharic acid and also can prepare as initial substance by crossing that phenmethyl 1-OH sugar is dissolved in the miscible organic solvent of non-water and in the presence of alkali and optional phase-transfer catalyst, reacting with the alkylating reagent of general formula X VIII

Nu-L-COO-SG (XVIII)，

Wherein Nu is a nucleofuge, and L is-(CH ₂)- _n(wherein n=1-5) ,-CH ₂-CHOH-or-CH (CHOH-CH ₂OH)-CHOH-CHOH-, and Sg represents protecting group.As nucleofuge, group-Cl ,-Br ,-J ,-OTs ,-OMs ,-OSO ₂CF ₃,-OSO ₂C ₄F ₉Or-OSO ₂C ₈F ₁₇Can be included in the alkylating reagent of general formula X VIII.

Protecting group is common sour protecting group.These protecting groups are (Protective Groups in Organic Syntheses, second edition, T.W.Greene and P.G.M.Wuts, the John Wiley ﹠amp that knows to those skilled in the art; Sons, Inc., New York 1991).

Reaction of the present invention can preferably be carried out to the temperature of room temperature at 0 ℃ at 0-50 ℃.Reaction times is 10 minutes to 24 hours, preferred 20 minutes to 12 hours.

With solid form, preferably with fine powder form or as 10-70%, the aqueous solution of preferred 30-50% adds with alkali.NaOH and KOH use as preferred bases.

In alkylation of the present invention, for example toluene, benzene, CF ₃-benzene, hexane, hexanaphthene, ether, tetrahydrofuran (THF), methylene dichloride, MTB or its mixture can be used as non-water miscibles organic solvent.

In the method for the invention, quaternary ammonium salt Huo phosphonium salt or the crown ether that becomes known for this purpose can be used as phase-transfer catalyst as [15]-hat-5 or [18]-hat-6.It is preferred suitable having four quaternary ammonium salts that are selected from the identical or different alkyl of methyl, ethyl, propyl group, sec.-propyl, butyl or isobutyl-on positively charged ion.Alkyl on the positively charged ion must be enough greatly to guarantee that alkylating reagent has good solvability in organic solvent.According to the present invention, especially preferably use N (butyl) ₄ ⁺-Cl ^-, N (butyl) ₄ ⁺-HSO ₄ ^-And N (methyl) ₄ ⁺-Cl ^-

The polyoxyethylene glycol acid that also can prepare corresponding terminal protection similarly.

Wherein L has the compound of the general formula (XI) of following implication,

By implication and L, X and R to make above-mentioned wetting ability carboxylic acid R and Sg wherein have protecting group according to acid amides formation method well known by persons skilled in the art _fAmine with general formula (XII) of above-mentioned implication reacts and prepares,

The compound of general formula (XII) passes through wherein R ⁸, R ^{8 '}, n ', W and m ' have single protection diamines that above-mentioned implication and Sg have the general formula (XIII) of protecting group implication

With wherein Y, G, s, s ' and ζ have above-mentioned implication, wherein Nu be nucleofuge general formula (XIV) contain the perfluor nucleophilic reagent

Nu—Y—(CH ₂) _s—(G) _t—(CH ₂) _s’—ζ

(XIV)

Reach reaction in the presence of the optional phase-transfer catalyst at alkali.As nucleofuge, group-Cl ,-Br ,-J ,-OTs ,-OMs ,-OSO ₂CF ₃,-OSO ₂C ₄F ₉Or-OSO ₂C ₈F ₁₇Can be included in the alkylating reagent of general formula X VIII.

Known general formula (XIV) contain the perfluor nucleophilic reagent and other contains the perfluoroalkyl material and their preparation is described in following publication:

J.G.Riess, Journal of Drug Targeting, 1994, the 2 volumes, 455-468 page or leaf;

People such as J.B.Nivet, Eur.J.Med.Chem., 1991, the 26 volumes, 953-960 page or leaf;

People such as M.-P.Krafft, Angew.Chem., 1994, the 106 volumes, the 10th phase, 1146-1148 page or leaf;

People such as M.Lanier, Tetrahedron Letters, 1995, the 36 volumes, the 14th phase, 2491-2492 page or leaf;

People such as F.Guillod, Carbohydrate Research, 1994, the 261 volumes, 37-55 page or leaf;

People such as S.Achilefu, Journal of Fluorine Chemistry, 1995, the 70 volumes, 19-26 page or leaf;

People such as L.Clary, Tetrahedron, 1995, the 51 volumes, the 47th phase, 13073-13088 page or leaf;

People such as F.Szoni, Journal of Fluorine Chemistry, 1989, the 42 volumes, 59-68 page or leaf;

People such as H.Wu, Supramolecular Chemistry, 1994, the 3 volumes, 175-180 page or leaf;

People such as F.Guileri, Angew.Chem.1994, the 106th volume, the 14th phase, 1583-1585 page or leaf;

People such as M.-P.Krafft, Eur.J.Med.Chem., 1991, the 26 volumes, 545-550 page or leaf;

People such as J.Greiner, Journal of Fluorine Chemistry, 1992, the 56 volumes, 285-293 page or leaf;

People such as A.Milius, Carbohydrate Research, 1992, the 229 volumes, 323-336 page or leaf;

People such as J.Riess, Colloids and Surfaces A, 1994, the 84 volumes, 33-48 page or leaf;

People such as G.Merhi, J.Med.Chem., 1996, the 39 volumes, 4483-4488 page or leaf;

People such as V.Cirkva, Journal of Fluorine Chemistry, 1997, the 83 volumes, 151-158 page or leaf;

People such as A.Ould Amanetoullah, Journal of Fluorine Chemistry, 1997, the 84 volumes, 149-153 page or leaf;

People such as J.Chen, Inorg.Chem., 1996, the 35 volumes, 1590-161 page or leaf;

People such as L.Clary, Tetrahedron Letters, 1995, the 36 volumes, the 4th phase, 539-542 page or leaf;

People such as M.M.Chaabouni, Journal of Fluorine Chemistry, 1990, the 46 volumes, 307-315 page or leaf;

People such as A.Milius, New J.Chem., 1991, the 15 volumes, 337-344 page or leaf;

People such as M.-P.Krafft, New J.Chem., 1990, the 14 volumes, 869-875 page or leaf;

People such as J.-B.Nivet, New J.Chem., 1994, the 18 volumes, 861-869 page or leaf;

People such as C.Santaella, New J.Chem., 1991, the 15 volumes, 685-692 page or leaf;

People such as C.Santaella, New J.Chem., 1992, the 16 volumes, 399-404 page or leaf;

People such as A.Milius, New J.Chem., 1992, the 16 volumes, 771-773 page or leaf;

People such as F.Sz  nyi, Journal of Fluorine Chemistry, 1991, the 55 volumes, 85-92 page or leaf;

People such as C.Santaella, Angew.Chem., 1991, the 103 volumes, the 5th phase, 584-586 page or leaf;

People such as M.-P.Krafft, Angew.Chem., 1993, the 105 volumes, the 5th phase, 783-785 page or leaf;

EP 0 548 096 B1。

Wherein L has the compound that following implication, q, α, β and γ have the general formula (XI) of above-mentioned implication

By making wherein X and R according to acid amides formation method well known by persons skilled in the art _fHave above-mentioned implication general formula (XV) contain perfluorocarboxylic acid

HO—X—R _f

(XV)

Have amine that above-mentioned implication and Sg have a general formula (XVI) of protecting group implication with wherein q, β and react and prepare,

The preparation of the compound of general formula (XV) contains the above-mentioned document that perfluorochemical quotes description is arranged being used for preparing.

Wherein q, β have above-mentioned implication and wherein Sg have the compound of the general formula (XVI) of protecting group implication

By make according to acid amides formation method well known by persons skilled in the art above-mentioned wetting ability amine R and q wherein have above-mentioned implication, Sg and Sg ' have the protecting group implication and wherein Sg and Sg ' in a different manner the carboxylic acid reaction of cracked general formula (XVII) prepare

The amino acid of these 2x-protections of general formula (XVII) is commercially available product (Bachem).

Compound according to the present invention is particularly suitable for NMR and x X-ray diagnosis X, radiodiagnosis and radiotherapy, and MRT lymphography and blood pool imaging.Contain that the perfluoroalkyl metal complex is particularly suitable for nuclear spin resonance tomography (MRT) thus being used to showing different physiology and physiopathology structure and improving diagnostic message for example disease location and degree, select and the success of monitoring therapeutic interest and be used for preventing disease and illness.

In an especially preferred embodiment, material according to the present invention is used for MRT lymphography.

In another particularly preferred embodiment, material according to the present invention is used for blood pool imaging.

Suitable disease and illness comprise tumor disease, particularly primary tumor, satellite shape metastasis, nodus lymphoideus transferring rate kitchen range and downright bad detection and sign, cardiovascular disorder, particularly caliber change, such as narrow and aneurysma, by detecting the arteriosclerosis of arteriosclerosis plaque, thrombotic disease, infraction, downright bad, inflammation, particularly sacroiliitis, osteomyelitis, ulcerative colitis, and god is damaged.

In particularly preferred embodiments, material according to the present invention is used for necrosis or tumor imaging.

Theme of the present invention is also for containing the medicine of normally used additive in compatible compound of at least a physiology according to the present invention and the optional galenical.

Compound of the present invention is characterised in that excellent consistency and excellent simultaneously video picture characteristic.Therefore, they are particularly suitable in MRT, particularly in MRT lymphography and systematicness use in tumor imaging.

According to the preparation of medicine of the present invention in mode as known in the art, be suspended in or be dissolved in the water medium by complex compound, choose wantonly then suspension or solution sterilization are carried out normally used additive in the optional interpolation galenical according to the present invention.Suitable additive for example be the harmless buffer reagent of physiology (such as trometamol), complexing agent or weak complex compound additive (such as diethylene triaminepentaacetic acid(DTPA) or with corresponding to Ca complex compound according to metal complex of the present invention), or if necessary, ionogen such as sodium-chlor; Or if necessary, antioxidant such as xitix.

If expectation is used for enteron aisle or administered parenterally or other purpose with the suspension or the solution of medicine according to the present invention in water or in the physiological salt solution, then with normally used auxiliary agent [for example methylcellulose gum, lactose, mannitol] in they and one or more galenical and/or surface drug [for example Yelkin TTS, Tween ^, Myrj ^] and/or the flavoring substance [for example volatile oil] that is used for flavoring mix.

In principle, also can not separate complex compound prepares according to medicine of the present invention.Under any circumstance, carry out the necessary SC of chelating, make complex compound according to the present invention be substantially free of the metal ion of not complexing with toxic action.

This can be guaranteed by control titration in preparation process by means of such as color indicators such as xylenol orange.Therefore, the invention still further relates to the method for preparing complex compound and salt thereof.As the last precautionary measures, still want the complex compound of purifies and separates.

Administration is according in the medicine of the present invention in vivo, can with described medicine with such as appropriate carriers such as serum or physiology customary salt solution and with such as human serum albumin other albumen administrations such as (HSA).

According to medicine of the present invention usually through parenteral, preferably through intravenous administration.Depend on and will check that the body blood vessel still organizes, they also can intravascular in or matter/intradermal administration.

Preferably contain the complex compound of 0.1 μ mol-2mol/l according to medicine of the present invention, and generally with the amount administration of 0.001-5mmol/kg.

Satisfy many requirements of the contrast medium that is suitable as the nuclear spin laminography video picture according to medicine of the present invention.Therefore behind per os or the administered parenterally, it is particularly well adapted for by increasing the value of information that strength of signal strengthens the image that is obtained by means of the nuclear spin laminography photography.The required good consistency of Noninvasive that they also show the unusual effect that a small amount of as far as possible foreign matter of body load of sening as an envoy to is required and keep these researchs.

Can prepare the dilution that highly concentrated solution remains in the rational limit with the volume load with the recycle system and remedies body fluid according to the good water-soluble and low osmolarity of medicine of the present invention is feasible.In addition, also demonstrate high astoundingly stability in high stability but also the body according to not only external the demonstrating of medicine of the present invention, therefore, inherent poisonous and ion bonding in complex compound only discharges extremely lentamente in the time that this novel type radiographic contrast is discharged fully again or exchanges.

Generally speaking, when medicine according to the present invention uses as the NMR diagnostic reagent, with 0.0001-5mmol/kg, the amount administration of preferred 0.005-0.5mmol/kg.

Also can be advantageously used for magnetizing reagent (susceptibility reagent) and the shift reagent that is used for NMR Spectrum Analysis in the body according to complex compound of the present invention.

Because according to the favourable radioactive nature and the good stability of the complex compound that is contained in the medicine of the present invention, so their also suitable radiodiagnosis agents of doing.The details of this application and dosage are in that for example " Radiotracers for Medical Applications, " CRC Press, BocaRaton have description among the Florida.

Also can be used for positron emission tomography according to compound of the present invention and medicine, described positron emission tomography uses the positron radiation isotropic substance, such as ⁴³Sc, ⁴⁴Sc, ⁵²Fe, ⁵⁵Co, ⁶⁸Ga reaches ⁸⁶Y (Heiss, W.D.; Phelps, M.E.; Positron EmissionTomography of Brain, Springer Verlag Berlin, Heidelberg, New York1983).

Histological research confirms that the capillary blood vessel local permeability is too high.

Therefore, also can be used for showing the unusual perviousness of kapillary according to contrast medium of the present invention.

The principal character according to compound of the present invention is that thereby they are fully from body discharge and better tolerance.Therefore, excellent video picture characteristic can be used, and the non-intruding character of diagnosis is maintained.

Because material according to the present invention accumulates in the malignant tumour (not at the health tissues internal diffusion, and tumor vessel being had hypertonicity), so they also can help the radiotherapy of malignant tumour.The radiotherapy of malignant tumour and the difference of corresponding diagnosis only are used isotopic amount and type.Order is to destroy tumour cell by the high energy short-wave radiation with minimum possibility sphere of action in the case.For this purpose, utilize metal contained in the complex compound (such as iron or gadolinium) and ionizing rays (for example x ray) or with the interaction of neutron ray.By this effect, significantly increase at the partial radiation dosage of the site that has metal complex.For in malignant tissue, producing identical radiation dose, also can avoid the side effect overweight to the patient thereby when using these metal complexs, can significantly reduce the radioactive exposure that is used for health tissues.Therefore, also be suitable for radiation sensitizing substance in the radiotherapy make pernicious tumour (for example use M  ssbauer effect or under the situation of neutron capture therapy) according to metal complex binding substances of the present invention (complex conjugates).Suitable β-emitting ions for example is ⁴⁶Sc, ⁴⁷Sc, ⁴⁸Sc, ⁷²Ga, ⁷³Ga reaches ⁹⁰Y.α-emitting ions with suitable low transformation period for example is ²¹¹Bi, ²¹²Bi, ²¹³Bi reaches ²¹⁴Bi, wherein preferred ²¹²Bi.Suitable photon and electron emission ion are ¹⁵⁸Gd, it can be by neutron death certainly ¹⁵⁷Gd obtains.

If be intended to medicine according to the present invention is used in the radiocurable variant that people such as R.L.Mills [Nature the 336th volume, (1988), the 787th page] are proposed, then central ion must be from M  β bauer isotropic substance, such as ⁵⁷Fe or ¹⁵¹Eu.

Administration is according in the medicine of the present invention in vivo, can with described medicine with such as appropriate carriers such as serum or physiology customary salt solution and with such as other albumen administrations such as human serum albumin.Dosage in this case depends on the type of cell fission type, used metal ion and developing method.

According to medicine of the present invention usually through parenteral, preferably through intravenous administration.As discussed above, depend on and will check that the body blood vessel still organizes, they also can intravascular in or matter/intradermal administration.

Be suitable as very much the x ray-contrast media according to medicine of the present invention, wherein want lay special stress in biological chemistry-pharmaceutical research, to use and to detect less than the known anaphylaxis symptom of self-contained iodine contrast agent according to medicine of the present invention.They are particularly useful to digital deshadowing technology owing to the favourable absorption characteristic in upper pipe pressure scope.

Generally speaking, when using as the x ray-contrast media that is similar to meglumin-urografic acid methylglucamine salt for example according to medicine of the present invention, with 0.1-5mmol/kg, the amount administration of preferred 0.25-1mmol/kg.

Used term among the application " metal ion Equivalent " is the Essential Terms in well known by persons skilled in the art, the chemistry of complex field.The metal ion Equivalent is the equivalent of metal ion, and it can be connected with for example carboxylate group rather than hydrogen.For example, if described metal is gadolinium, then Gd ³⁺Can be connected with 3 carboxylate groups, i.e. 1/3Gd ³⁺Corresponding to formula (II), (III), (IV) or the metal ion Equivalent R (V) ¹

Embodiment

Embodiment 1

A) 1-N-(carbobenzoxy-(Cbz))-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-azepine-perfluor tridecyl amine

With 23.31g (120mmol) N-carbobenzoxy-(Cbz)-quadrol (people such as Atwell, Synthesis, 1984,1032-1033) and 10.2g (100mmol) triethylamine add as for 54.22g (100mmol) methylsulfonic acid-(1H, the 1H in 500 milliliters of acetonitriles, 2H, 2H-perfluor decyl)-ester (people such as Bartsch, Tetrahedron, 2000,3291-3302), and under 60 ℃, stirred 48 hours.Indissolvable component is leached from reaction soln, in a vacuum it is evaporated to drying regime, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless wax of output: 32.8g (theoretical amount 51%)

Ultimate analysis:

Calculated value: C 37.51 H 2.68 N 4.37 F 50.44

Measured value: C 37.82 H 2.74 N 4.29 F 50.27

B) N-[2-(carbobenzoxy-(Cbz))-amino-ethyl-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-[1-O-α-d-(2,3,4,6-four-O-benzyl) mannopyranose base]-ethanamide

Under 0 ℃, 8.05g (39.04mmol) dicyclohexylcarbodiimide is added into the title compound of embodiment 1a of 20g (31.23mmol) and 1-O-α-d-carbonyl methyl-(2 of 18.70g (31.23mmol), 3,4,6-four-O-benzyl) in the solution of N-maloyl imines in the 200ml dimethyl formamide of mannopyranose (prepared) and 3.59g (31.23mmol) according to WO 99/01160A1, stirred 3 hours down at 0 ℃, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 29.8g (theoretical amount 78%).

Ultimate analysis:

Calculated value: C 55.09 H 4.38 N 2.29 F 26.45

Measured value: C 55.27 H 4.40 N 2.24 F 26.31

C) N-(2-amino-ethyl)-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-(1-O-alpha-d-galactopy mannose group)-ethanamide, mesylate

2.29g (23.75mmol) methylsulfonic acid and 4.0g palladium catalyst (10% Pd/C) are added in the solution of title compound in 500ml ethanol of embodiment 1b of 29g (23.75mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 19.5g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 30.67 H 3.31 N 3.41 F 39.27

Measured value: C 31.01 H 3.29 N 3.33 F 39.04

D) N-{[1,4,7-three (carboxymethyl)-1,4; 7,10-Fourth Ring dodecane-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H, 1H; 2H, 2H-perfluor decyl)-2-(1-O-alpha-d-galactopy mannose group)-ethanamide, the Gd complex compound

Under mild heat, title compound, 2.61g (22.72mmol) N-maloyl imines, 1.93g (45.44mmol) lithium chloride and 14.31g (22.72mmol) 1 with the embodiment 1c of 18.7g (22.72mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG, (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Add 5.86g (28.4mmol) dicyclohexylcarbodiimide and 2.30g (22.72mmol) triethylamine down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 22.3g (theoretical amount 68%) colorless solid

Water content (Karl-Fischer): 7.0%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 35.01 H 3.84 N 7.33 F 24.14 Gd 11.75

Measured value: C 35.21 H 3.89 N 7.27 F 24.09 Gd 11.61

Embodiment 2

A) 1-N-(carbobenzoxy-(Cbz))-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-N-[1,4,7-three (carboxymethyl)-1,4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the perfluor tridecyl amine, the Gd complex compound

Under mild heat, title compound, 1.80g (15.62mmol) N-maloyl imines, 1.33g (31.34mmol) lithium chloride and 9.84g (15.62mmol) 1 with the embodiment 1a of 10.0g (15.62mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG, (embodiment 1)) is dissolved in the 150ml methyl-sulphoxide.Add 4.03g (19.52mmol) dicyclohexylcarbodiimide down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml ether and stirred other 10 minutes.Precipitated solid is leached, then residue is carried out silica gel chromatography (mobile solvent: methylene chloride/ammoniacal liquor 10: 5: 1).

Output: 16.4g (theoretical amount 79%) colorless solid

Water content (Karl-Fischer): 5.4%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 37.41 H 3.62 N 7.83 F 25.80 Gd 12.56

Measured value: C 37.69 H 3.56 N 7.91 F 25.64 Gd 12.37

B) 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-N-[1,4,7-three-(carboxymethyl)-1,4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the perfluor tridecyl amine, Gd complex compound, mesylate

1.16g (12.08mmol) methylsulfonic acid and 2.0g palladium catalyst (10% Pd/C) are added in the solution of title compound in 300ml ethanol of embodiment 2a of 16g (12.08mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 15.8g (quantitative) colorless solid.

Water content (Karl-Fischer): 7.0%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 31.66 H 3.57 N 8.08 F 26.60 Gd 12.95

Measured value: C 31.88 H 3.59 N 8.14 F 26.42 Gd 12.69

C) 1H, 1H, 2H, 2H, 4H; 4H, 5H, 5H-3-N-[1,4,7-three-(carboxymethyl)-1; 4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-perfluor tridecyl-N-2-(1-O-alpha-d-galactopy mannose group)-ethanamide, the Gd complex compound

Under 0 ℃, 1.72g (8.33mmol) dicyclohexylcarbodiimide and 674mg (6.66mmol) triethylamine are added into title compound and 3.99g (6.66mmol) 1-O-α-d-carbonyl methyl-(2 of the embodiment 2b of 8.9g (6.66mmol), 3,4,6-four-O-benzyl) in mannopyranose (prepared) and the solution of 767mg (6.66mmol) N-maloyl imines in the 100ml dimethyl formamide according to WO 99/01160 A1, stirred 3 hours down at 0 ℃, at room temperature stirred then 16 hours.To precipitate urea and leach, and in a vacuum filtrate will be evaporated to drying regime.Residue is dissolved in the 100ml methyl alcohol, mixes also hydrogenation at room temperature 24 hours with 2.0g palladium catalyst (10% Pd/C).Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.Residue is absorbed with less water, indissolvable component is leached, then filtrate is passed through chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 6.1g (theoretical amount 64%) colorless solid

Water content (Karl-Fischer): 6.2%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 35.01 H 3.84 N 7.33 F 24.14 Gd 11.75

Measured value: C 35.23 H 3.88 N 7.27 F 24.01 Gd 11.59

Embodiment 3

A) [1,3-pair-(2-benzyloxy-1-benzyloxymethyl-oxyethyl group)-third-2-yl]-acetate

Under 0 ℃, 14.62g (75mmol) bromo-acetic acid tert-butyl is added into 250 milliliters of 30.02g (50mmol) 1 in the toluene, 3-is two-(2-benzyloxy-1-benzyloxymethyl-oxyethyl group)-propan-2-ol (people such as Cassel, Eur.J.Org.Chem., 2001,5,875-896) with the 4-n-butyl ammonium hydrogen sulfate of 5.6g (100mmol) potassium hydroxide fine powder and catalytic amount (1g) in, and under this temperature, stirred 2 hours and at room temperature stirred 12 hours.Reaction soln is mixed with 500ml ethyl acetate and 300ml water.Organic phase is separated, and,, and in a vacuum it is evaporated to drying regime then through dried over mgso with each 300ml water washing twice.Residue is suspended in the mixture of being made up of with 2: 1 ratios 400ml methyl alcohol and 0.5M sodium hydroxide solution, heated then 12 hours to 60 ℃.With reaction mixture by with Amberlite IR 120 (H ⁺Type) the Zeo-karb mixing is neutralized so that handle, and exchanger is leached, is evaporated to drying regime, and carry out silica gel chromatography (mobile solvent: ethyl acetate/hexane 1: 3).

The colourless wax of output: 23.5g (theoretical amount 71%)

Ultimate analysis:

Calculated value: C 71.10 H 7.04

Measured value: C 71.29 H 7.21

B) N-[2-(carbobenzoxy-(Cbz))-amino-ethyl-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-[1,3-pair-(2-benzyloxy-1-benzyloxymethyl-oxyethyl group)-third-2-oxygen base]-ethanamide

Under 0 ℃, 8.05g (39.04mmol) dicyclohexylcarbodiimide is added in the title compound and the solution of 3.59g (31.23mmol) N-maloyl imines in the 200ml dimethyl formamide of embodiment 3a of the title compound of embodiment 1a of 20g (31.23mmol) and 20.57g (31.23mmol), and under 0 ℃, stirred 3 hours, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 28.7g (theoretical amount 72%).

Ultimate analysis:

Calculated value: C 55.32 H 4.80 N 2.19 F 25.21

Measured value: C 55.56 H 4.87 N 2.13 F 26.07

C) N-(2-amino-ethyl)-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-[1,3-pair-(2-hydroxyl-1-methylol-oxyethyl group)-third-2-oxygen base]-ethanamide, mesylate

1.96g (20.29mmol) methylsulfonic acid and 4.0g palladium catalyst (10%Pd/C) are added in the solution of title compound in 500ml ethanol of embodiment 3b of 26g (20.29mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 17.9g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 32.66 H 4.00 N 3.17 F 36.59

Measured value: C 32.89 H 4.10 N 3.11 F 36.41

D) N-{[1; 4; 7-three-(carboxymethyl)-1,4,7; 10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H; 1H, 2H, 2H-perfluor decyl)-2-[1; 3-pair-(2-hydroxyl-1-methylol-oxyethyl group)-third-2-oxygen base]-ethanamide, the Gd complex compound

Under mild heat, title compound, 2.19g (19.07mmol) N-maloyl imines, 1.62g (38.14mmol) lithium chloride and 14.31g (19.07mmol) 1 with the embodiment 3c of 16.8g (19.07mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Add 4.92g (23.84mmol) dicyclohexylcarbodiimide and 1.93g (19.07mmol) triethylamine down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 20.6g (theoretical amount 72%) colorless solid

Water content (Karl-Fischer): 6.7%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.06 H 4.25 N 7.01 F 23.10 Gd 11.25

Measured value: C 36.34 H 4.32 N 6.97 F 22.88 Gd 11.17

Embodiment 4

A) 1,4,7-{ three (carboxymethyl)-10-[(3-azepine-4-oxo-oneself-the 5-yl) acid-N-1H, 1H; 2H, 2H, 4H; 4H, 5H, 5H-3-N-[1; 4,7-three-(carboxymethyl)-1,4; 7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-perfluor tridecyl acid amides]-1,4; 7,10-tetraazacyclododecanand, Gd complex compound

Under mild heat, title compound, 726mg (6.31mmol) N-maloyl imines, 535mg (12.62mmol) lithium chloride and 3.97g (6.31mmol) 1 with the embodiment 2b of 8.1g (6.31mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 100ml methyl-sulphoxide.Add 1.63g (7.89mmol) dicyclohexylcarbodiimide and 693mg (6.31mmol) triethylamine down at 10 ℃, and at room temperature stirred 16 hours.Solution is poured into 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 6.5g (theoretical amount 56%) colorless solid

Water content (Karl-Fischer): 5.8%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 34.72 H 3.90 N 9.72 F 18.67 Gd 18.18

Measured value: C 34.94 H 3.94 N 9.67 F 18.59 Gd 18.01

Embodiment 5

A) N-[2-(carbobenzoxy-(Cbz))-amino-ethyl-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-[2-(2-methoxy ethoxy)-oxyethyl group]-ethanamide

Under 0 ℃, 8.05g (39.04mmol) dicyclohexylcarbodiimide is added in the title compound of embodiment 1a of 20g (31.23mmol) and 5.57g (31.23mmol) [2-(2-methoxy ethoxy)-oxyethyl group]-acetate (Aldrich) and the solution of 3.59g (31.23mmol) N-maloyl imines in the 200ml dimethyl formamide, and under 0 ℃, stirred 3 hours, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 19.8g (theoretical amount 79%).

Ultimate analysis:

Calculated value: C 40.51 H 3.65 N 3.50 F 40.35

Measured value: C 40.62 H 3.68 N 3.53 F 40.09

B) N-(2-amino-ethyl)-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-[2-(2-methoxy ethoxy) oxyethyl group]-ethanamide, mesylate

2.28g (23.73mmol) methylsulfonic acid and 4.0g palladium catalyst (10% Pd/C) are added in the solution of title compound in 500ml ethanol of embodiment 5a of 19g (23.73mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 18.1g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 31.51 H 3.57 N 3.67 F 42.36

Measured value: C 31.77 H 3.59 N 3.54 F 42.05

C) N-{[1,4,7-three-(carboxymethyl)-1,4; 7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H, 1H; 2H, 2H-perfluor decyl)-2-[2-(2-methoxy ethoxy)-oxyethyl group]-ethanamide, the Gd complex compound

Under mild heat, title compound, 2.59g (22.51mmol) N-maloyl imines, 1.91g (45.02mmol) lithium chloride and 14.18g (22.51mmol) 1 with the embodiment 5b of 17.2g (22.51mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Add 5.81g (28.14mmol) dicyclohexylcarbodiimide and 2.28g (22.51mmol) triethylamine down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 21.5g (theoretical amount 70%) colorless solid

Water content (Karl-Fischer): 6.4%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 35.71 H 4.02 N 7.67 F 25.72 Gd 12.30

Measured value: C 35.79 H 4.07 N 7.59 F 25.63 Gd 12.27

Embodiment 6

A) 1-N-(carbobenzoxy-(Cbz))-1H, 1H, 2H, 2H, 5H, 5H, 7H, 7H, 8H, 8H-3-azepine-4-oxa--6-oxo-perfluor cetylamine

17.8g (140mmol) oxalyl chloride is added into 52.22g (100mmol) 2H in the 500ml methylene dichloride, 2H, 4H, 4H, 5H in the 5H-3-oxa--perfluor tridecylic acid (according to EP 01/08498 preparation), and at room temperature stirred 14 hours.Be evaporated to drying regime in a vacuum, residue is dissolved in the 400ml methylene dichloride, at 0 ℃ down and 23.31g (120mmol) N-carbobenzoxy-(Cbz)-quadrol (people such as Atwell, Synthesis, 1984,1032-1033) and 10.2g (100mmol) triethylamine mix, and at room temperature stirred 24 hours.With reaction soln and 400ml 1N mixed in hydrochloric acid and abundant the stirring 15 minutes.Organic phase is separated,, and be evaporated to drying regime in a vacuum through dried over mgso.Residue is carried out silica gel chromatography (mobile solvent: ethyl acetate/hexane 1: 2).

The colourless wax of output: 49.7g (theoretical amount 71%)

Ultimate analysis:

Calculated value: C 37.84 H 2.74 N 4.01 F 46.25

Measured value: C 38.02 H 2.76 N 3.97 F 46.12

B) 1-N-(carbobenzoxy-(Cbz))-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H, 7H, 7H, 8H, 8H-3-azepine-6-oxo-perfluor cetylamine

The title compound of the embodiment 6a of 48.5g among the 150ml THF (69.45mmol) is mixed with 50ml 10M borine methyl-sulfide (in THF), and refluxed 5 hours.Be cooled to 0 ℃, drip 100ml methyl alcohol, at room temperature stirred 1 hour, in a vacuum it is evaporated to drying regime then.Use mixture to absorb residue, and stirred 14 hours down at 40 ℃ by 300ml ethanol/50ml 1M hydrochloric acid is formed.Be evaporated to drying regime in a vacuum, residue is absorbed with 300ml 5% sodium hydroxide solution, and with each 300ml dichloromethane extraction three times.The organic phase that merges through dried over mgso, is evaporated to drying regime in a vacuum, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 10: 1).

Output: 39.8g (theoretical amount 84%) colorless solid

Ultimate analysis:

Calculated value: C 38.61 H 3.09 N 4.09 F 47.19

Measured value: C 38.88 H 3.14 N 4.06 F 46.87

C) N-[2-(carbobenzoxy-(Cbz))-amino-ethyl-N-(1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa--perfluor tridecyl)-2-[2-(2-methoxy ethoxy)-oxyethyl group]-ethanamide

Under 0 ℃, 7.54g (36.53mmol) dicyclohexylcarbodiimide is added in the title compound of embodiment 6b of 20g (29.22mmol) and 5.21g (29.22mmol) [2-(2-methoxy ethoxy)-oxyethyl group]-acetate (Aldrich) and the solution of 3.36g (29.22mmol) N-maloyl imines in the 200ml dimethyl formamide, and under 0 ℃, stirred 3 hours, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 18.3g (theoretical amount 74%).

Ultimate analysis:

Calculated value: C 41.24 H 3.94 N 3.32 F 38.24

Measured value: C 41.42 H 3.98 N 3.33 F 38.21

D) N-(2-amino-ethyl)-N-(1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa--perfluor tridecyl)-2-[2-(2-methoxy ethoxy)-oxyethyl group]-ethanamide, mesylate

2.0g (20.72mmol) methylsulfonic acid and 3.0g palladium catalyst (10% Pd/C) are added in the solution of title compound in 300ml ethanol of embodiment 6c of 17.5g (20.72mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 16.7g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 32.76 H 3.87 N 3.47 F 40.04

Measured value: C 32.99 H 3.98 N 3.35 F 39.84

E) N-{[1,4,7-three-(carboxymethyl)-1; 4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H; 1H; 2H, 2H, 4H; 4H; 5H, 5H-3-oxa--perfluor tridecyl)-2-[2-(2-methoxy ethoxy)-oxyethyl group]-ethanamide, the Gd complex compound

Under mild heat, title compound, 2.11g (18.30mmol) N-maloyl imines, 1.55g (36.60mmol) lithium chloride and 11.52g (18.30mmol) 1 with the embodiment 6d of 14.8g (18.30mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Add 4.72g (22.88mmol) dicyclohexylcarbodiimide and 1.85g (18.30mmol) triethylamine down at 10 ℃, and at room temperature stirred 16 hours.Solution is poured into 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 16.6g (theoretical amount 64%) colorless solid

Water content (Karl-Fischer): 6.9%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.34 H 4.19 N 7.42 F 24.43 Gd 11.89

Measured value: C 36.49 H 4.27 N 7.36 F 24.28 Gd 11.78

Embodiment 7

A) 6-N-carbobenzoxy-(Cbz)-2-N-(2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluor tridecanoyl)-L-Methionin

With 25g (31.31mmol) 6-N-carbobenzoxy-(Cbz)-2-N-(2H, 2H, 4H; 4H; 5H, 5H-3-oxa-perfluor tridecanoyl)-L-lysine methyl ester (according to EP 03/07274 preparation) is dissolved in 200ml methyl alcohol and the 50ml 2N potassium hydroxide solution, and at room temperature stirred 18 hours.It with the 2N hcl acidifying, is evaporated to drying regime, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 10: 1).

Output: 22.4g (theoretical amount 91%) colorless solid

Ultimate analysis:

Calculated value: C 39.81 H 3.21 N 3.57 F 41.17

Measured value: C 40.07 H 3.27 N 3.49 F 41.05

B) [1-O-α-d-(2,3,4,6-four-O-benzyl) mannopyranose base]-ethanamide

11.45g (90mmol) oxalyl chloride is added into 40g (66.81mmol) 1-O-α-d-carbonyl methyl-(2,3,4,6-four-O-benzyl) mannopyranose in the 300ml methylene dichloride (according to WO 99/01160 A1 preparation), and at room temperature stirred 14 hours.Be evaporated to drying regime in a vacuum, residue is dissolved in the 400ml methylene dichloride, under 0 ℃, ammonia introduced in the solution about 2 hours, and at room temperature stirred 4 hours.With reaction soln and 400ml 1N mixed in hydrochloric acid and abundant the stirring 15 minutes.Organic phase is separated,, and be evaporated to drying regime in a vacuum through dried over mgso.Residue is carried out silica gel chromatography (mobile solvent: ethyl acetate/hexane 1: 2).

Output: 34.1g (theoretical amount 85%) colorless oil

Ultimate analysis:

Calculated value: C 72.34 H 6.58 N 2.34

Measured value: C 72.69 H 6.54 N 2.39

C) 2-[1-O-α-d-(2,3,4,6-four-O-benzyl) mannopyranose base]-ethamine

The title compound of the embodiment 7b of 33g among the 100ml THF (55.21mmol) is mixed with 30ml 10M borine methyl-sulfide (in THF), and refluxed 5 hours.Be cooled to 0 ℃, drip 100ml methyl alcohol, at room temperature stirred 1 hour, be evaporated to drying regime then in a vacuum.Use mixture to absorb residue, and stirred 14 hours down at 60 ℃ by 200ml ethanol/the 100ml thanomin is formed.Be evaporated to drying regime in a vacuum, residue is absorbed with 300ml 5% sodium hydroxide solution, and with each 300ml dichloromethane extraction three times.The organic phase that merges through dried over mgso, is evaporated to drying regime in a vacuum, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 10: 1).

Output: 26.2g (theoretical amount 81%) colorless solid

Ultimate analysis:

Calculated value: C 74.08 H 7.08 N 2.40

Measured value: C 74.55 H 7.19 N 2.31

D) 6-N-carbobenzoxy-(Cbz)-2-N-(2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluor tridecanoyl)-L-Methionin-{ 2-[1-O-α-d-(2,3,4,6-four-O-benzyl) mannopyranose base]-ethyl }-acid amides

Under 0 ℃, 4.93g (23.90mmol) dicyclohexylcarbodiimide is added in the title compound and the solution of 2.20g (19.12mmol) N-maloyl imines in the 200ml dimethyl formamide of embodiment 7c of the title compound of embodiment 7a of 15g (19.12mmol) and 11.16g (19.12mmol), and under 0 ℃, stirred 3 hours, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 19.2g (theoretical amount 74%).

Ultimate analysis:

Calculated value: C 55.15 H 4.78 N 3.11 F 23.92

Measured value: C 55.32 H 4.82 N 3.09 F 23.74

E) 2-N-(2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluor tridecyl)-L-Methionin-[2-{1-O-alpha-d-galactopy mannose group }-ethyl-acid amides

2.0g palladium catalyst (10% Pd/C) is added in the solution of title compound in 200ml ethanol of embodiment 7d of 18.5g (13.70mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 11.8g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 36.50 H 4.01 N 4.91 F 37.75

Measured value: C 36.79 H 3.98 N 4.87 F 37.84

F) 6-N-[1; 4,7-three-(carboxymethyl)-1,4; 7; 10 tetraazacyclododecanands-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-2-N-(2H, 2H, 4H; 4H; 5H, 5H-3-oxa-perfluor tridecanoyl)-L-Methionin-[2-{1-O-alpha-d-galactopy mannose group }-ethyl }-acid amides, the Gd complex compound

Under mild heat, title compound, 1.48g (12.86mmol) N-maloyl imines, 1.09g (25.72mmol) lithium chloride and 8.10g (12.86mmol) 1 with the embodiment 7e of 11.0g (12.86mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 100ml methyl-sulphoxide.Add 3.32g (16.08mmol) dicyclohexylcarbodiimide down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 13.0g (theoretical amount 64%) colorless solid

Water content (Karl-Fischer): 6.9%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.84 H 4.26 N 7.64 F 22.01 Gd 10.72

Measured value: C 37.03 H 4.31 N 7.59 F 21.95 Gd 10.62

Embodiment 8

A) 6-N-carbobenzoxy-(Cbz)-2-N-(2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluor tridecanoyl)-L-Methionin-{ [N-(2S, 3R, 4R, 5R)-2,3,4,5,6-penta hydroxy group hexyl]-N-methyl }-acid amides

Under 0 ℃, 4.93g (23.90mmol) dicyclohexylcarbodiimide is added in the title compound of embodiment 7a of 15g (19.12mmol) and 5.6g (28.68mmol) N-methylglucosamine (Aldrich) and the solution of 2.20g (19.12mmol) N-maloyl imines in the 200ml dimethyl formamide, and under 0 ℃, stirred 3 hours, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 5: 1).

The colourless heavy-gravity oily matter of output: 9.4g (theoretical amount 51%).

Ultimate analysis:

Calculated value: C 41.22 H 4.19 N 4.37 F 33.58

Measured value: C 41.47 H 4.30 N 4.29 F 33.35

B) 2-N-(2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluor tridecanoyl)-L-Methionin-{ [N-(2S, 3R, 4R, 5R)-2,3,4,5,6-penta hydroxy group hexyl]-N-methyl }-acid amides

1.0g palladium catalyst (10% Pd/C) is added in the solution of title compound in 100ml ethanol of embodiment 8a of 9.0g (9.39mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 7.8g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 36.29 H 4.14 N 5.08 F 39.03

Measured value: C 36.44 H 4.17 N 4.98 F 38.86

C) 6-N-[1,4,7-three-(carboxymethyl)-1,4; 7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-2-N-(2H, 2H; 4H, 4H, 5H; 5H-3-oxa-perfluor tridecanoyl)-L-Methionin-{ [N-(2S, 3R, 4R; 5R)-2,3,4; 5,6-penta hydroxy group hexyl]-the N-methyl }-acid amides, the Gd complex compound

Under mild heat, title compound, 974mg (8.46mmol) N-maloyl imines, 717mg (16.92mmol) lithium chloride and 5.33g (8.46mmol) 1 with the embodiment 8b of 7.0g (8.46mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 100ml methyl-sulphoxide.Under 10 ℃, add 2.18g (10.57mmol) dicyclohexylcarbodiimide, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 7.4g (theoretical amount 57%) colorless solid

Water content (Karl-Fischer): 6.1%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.72 H 4.34 N 7.79 F 22.44 Gd 10.93

Measured value: C 36.87 H 4.36 N 7.72 F 22.48 Gd 10.94

Embodiment 9

A) 6-N-carbobenzoxy-(Cbz)-2-N-(2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluor tridecanoyl)-L-Methionin-(2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group-ethyl)-acid amides

Under 0 ℃, 4.93g (23.90mmol) dicyclohexylcarbodiimide is added into the title compound of embodiment 7a of 15g (19.12mmol) and 3.97g (19.12mmol) (2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group-ethyl)-amine (people such as Whitessides, JACS, 1994,5057-5062) with the solution of 2.20g (19.12mmol) N-maloyl imines in the 200ml dimethyl formamide in, and under 0 ℃, stirred 3 hours, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 10: 1).

The colourless heavy-gravity oily matter of output: 12.2g (theoretical amount 82%).

Ultimate analysis:

Calculated value: C 43.17 H 4.55 N 4.32 F 33.17

Measured value: C 43.36 H 4.61 N 4.27 F 33.00

B) 2-N-(2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluor tridecanoyl)-L-Methionin-(2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group-ethyl)-acid amides

1.0g palladium catalyst (10% Pd/C) is added in the solution of title compound in 100ml ethanol of embodiment 9a of 11.5g (11.81mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 9.95g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 38.63 H 4.56 N 5.00 F 38.47

Measured value: C 38.75 H 4.61 N 4.93 F 38.27

C) 6-N-[1; 4,7-three-(carboxymethyl)-1,4; 7; 10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl]-2-N-(2H, 2H, 4H; 4H; 5H, 5H-3-oxa-perfluor tridecanoyl-L-Methionin-(2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethyl)-acid amides, the Gd complex compound

Under mild heat, title compound, 1.23g (10.72mmol) N-maloyl imines, 909mg (21.44mmol) lithium chloride and 6.75g (10.72mmol) 1 with the embodiment 9b of 9.0g (10.72mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 100ml methyl-sulphoxide.Add 2.76g (13.4mmol) dicyclohexylcarbodiimide down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 10.1g (theoretical amount 62%) colorless solid

Water content (Karl-Fischer): 6.0%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.21 H 4.17 N 6.87 F 22.65 Gd 11.03

Measured value: C 36.41 H 4.22 N 6.79 F 22.58 Gd 10.92

Embodiment 10

A) 2H, 2H, 4H, 4H-3-oxa--perfluor dodecylic acid

Under 0 ℃, 64.96g (333.26mmol) bromo-acetic acid tert-butyl is added into 100g (222.17mmol) 1H in the 800ml toluene, four of 1H-perfluor-1 nonyl alcohol (Apollo) and 24.9g (444mmol) potassium hydroxide fine powder and catalytic amount (2g)-positive butyl hydrogen sulfate hydrogen ammonium, and under this temperature, stirred 2 hours, and at room temperature stirred 12 hours.Reaction soln is mixed with 1500ml ethyl acetate and 800ml water.Organic phase is separated, and,, and be evaporated to drying regime in a vacuum then through dried over mgso with each 500ml water washing twice.Residue is suspended in the mixture of being made up of with 2: 1 ratios 1200ml methyl alcohol and 0.5M sodium hydroxide solution, was heated to 60 ℃ through 12 hours then.With reaction mixture by with Amberlite IR 120 (H ⁺Type) Zeo-karb mixes and neutralizes to handle, and exchanger is leached, and is evaporated to drying regime, and carries out silica gel chromatography (mobile solvent: ethyl acetate/hexane 1: 3).

The colourless wax of output: 87g (theoretical amount 77%)

Ultimate analysis:

Calculated value: C 26.00 H 0.99 F 63.56

Measured value: C 26.22 H 1.01 F 63.42

B) 1-N-(carbobenzoxy-(Cbz))-1H, 1H, 2H, 2H, 5H, 5H, 7H, 7H-3-azepine-4-oxa--6-oxo-perfluor amyl group decyl amine

17.8g (140mmol) oxalyl chloride is added in the title compound of embodiment 10a of the 50.81g (100mmol) in the 500ml methylene dichloride, and at room temperature stirred 14 hours.Be evaporated to drying regime in a vacuum, residue is dissolved in the 400ml methylene dichloride, at 0 ℃ down and 23.31g (120mmol) N-carbobenzoxy-(Cbz)-quadrol (people such as Atwell, Synthesis, 1984,1032-1033) and 10.2g (100mmol) triethylamine mix, and at room temperature stirred 24 hours.With reaction soln and 400ml 1N mixed in hydrochloric acid and abundant the stirring 15 minutes.Organic phase is separated,, and be evaporated to drying regime in a vacuum through dried over mgso.Residue is carried out silica gel chromatography (mobile solvent: ethyl acetate/hexane 1: 2).

The colourless wax of output: 46.5g (theoretical amount 68%)

Ultimate analysis:

Calculated value: C 36.86 H 2.50 N 4.09 F 47.19

Measured value: C 37.00 H 2.52 N 4.11 F 46.97

C) 1-N-(carbobenzoxy-(Cbz))-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H, 7H, 7H-3-azepine-6-oxo-perfluor pentadecyl amine

The title compound of the embodiment 10b of 45.5g among the 150ml THF (66.40mmol) is mixed with the 10M borine methyl-sulfide (in THF) of 50ml, and refluxed 5 hours.Be cooled to 0 ℃, drip 100ml methyl alcohol, at room temperature stirred 1 hour, be evaporated to drying regime then in a vacuum.Use the mixture of forming by the 1M hydrochloric acid of 300ml ethanol/50ml to absorb residue, and stirred 14 hours down at 40 ℃.Be evaporated to drying regime in a vacuum, residue is absorbed with 5% sodium hydroxide solution of 300ml, and with each 300ml dichloromethane extraction three times.The organic phase that merges through dried over mgso, is evaporated to drying regime in a vacuum, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 10: 1).

Output: 35.2g (theoretical amount 79%) colorless solid

Ultimate analysis:

Calculated value: C 37.63 H 2.86 N 4.18 F 48.18

Measured value: C 37.87 H 2.90 N 4.17 F 48.00

D) N-[2-(carbobenzoxy-(Cbz))-amino-ethyl-N-(1H, 1H, 2H, 2H, 4H, 4H-3-oxa-perfluor dodecyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide

Under 0 ℃, 7.69g (37.29mmol) dicyclohexylcarbodiimide is added into { 2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-acetate (people such as Voegtle of the title compound of embodiment 10c of 20g (29.83mmol) and 6.63g (29.83mmol), LiebigsAnn.Chem., 1980,858-862) with the solution of 3.43g (29.83mmol) N-maloyl imines in the 200ml dimethyl formamide in, and under 0 ℃, stirred 3 hours, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 20.1g (theoretical amount 77%).

Ultimate analysis:

Calculated value: C 41.20 H 4.03 N 3.20 F 36.93

Measured value: C 41.44 H 3.98 N 3.11 F 36.84

E) N-(2-amino-ethyl)-N-(1H, 1H, 2H, 2H, 4H, 4H-3-oxa--perfluor dodecyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, mesylate

2.09g (21.72mmol) methylsulfonic acid and 3.0g palladium catalyst (10% Pd/C) are added in the solution of title compound in 300ml ethanol of embodiment 10d of 19.0g (21.72mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 18.2g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 33.02 H 3.98 N 3.35 F 38.61

Measured value: C 33.41 H 3.96 N 3.25 F 38.44

F) N-{[1; 4,7-three-(carboxymethyl)-1,4; 7; 10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H, 1H, 2H; 2H; 4H, 4H-3-oxa--perfluor dodecyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Gd complex compound

Under mild heat, title compound, 2.18g (18.9mmol) N-maloyl imines, 1.60g (37.80mmol) lithium chloride and 11.90g (18.30mmol) 1 with the embodiment 10e of 15.8g (18.9mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Add 4.87g (23.63mmol) dicyclohexylcarbodiimide and 1.91g (18.9mmol) triethylamine down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 16.7g (theoretical amount 61%) colorless solid

Water content (Karl-Fischer): 6.9%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.42 H 4.25 N 7.25 F 23.89 Gd 11.63

Measured value: C 36.71 H 4.32 N 7.19 F 23.67 Gd 11.51

Embodiment 11

17.8g (140mmol) oxalyl chloride is added into 52.21g (100mmol) 2H in the 500ml methylene dichloride, 2H, 4H, 4H, 5H, 5H-3-oxa--perfluor tridecylic acid (the embodiment 39g of EP 01/08498), and at room temperature stirred 14 hours.Be evaporated to drying regime in a vacuum, residue is dissolved in the 400ml methylene dichloride, at 0 ℃ down and 23.31g (120mmol) N-carbobenzoxy-(Cbz)-quadrol (people such as Atwell, Synthesis, 1984,1032-1033) and 10.2g (100mmol) triethylamine mix, and at room temperature stirred 24 hours.With reaction soln and 400ml 1N mixed in hydrochloric acid and abundant the stirring 15 minutes.Organic phase is separated,, and be evaporated to drying regime in a vacuum through dried over mgso.Residue is carried out silica gel chromatography (mobile solvent: ethyl acetate/hexane 1: 2).

The colourless wax of output: 49.6g (theoretical amount 71%)

Ultimate analysis:

Calculated value: C 37.84 H 2.74 N 4.01 F 46.25

Measured value: C 37.99 H 2.81 N 4.05 F 45.96

The title compound of the embodiment 11a of 48.0g among the 150ml THF (68.73mmol) is mixed with 50ml 10M borine methyl-sulfide (in THF), and refluxed 5 hours.Be cooled to 0 ℃, drip 100ml methyl alcohol, at room temperature stirred 1 hour, be evaporated to drying regime then in a vacuum.Use mixture to absorb residue, and stirred 14 hours down at 40 ℃ by 300ml ethanol/50ml 1M hydrochloric acid is formed.Be evaporated to drying regime in a vacuum, residue is absorbed with 5% sodium hydroxide solution of 300ml, and with each 300ml dichloromethane extraction three times.The organic phase that merges through dried over mgso, is evaporated to drying regime in a vacuum, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 10: 1).

Output: 30.2g (theoretical amount 64%) colorless solid

Ultimate analysis:

Calculated value: C 36.61 H 3.09 N 4.09 F 47.19

Measured value: C 36.77 H 3.14 N 4.02 F 46.99

C) N-[2-(carbobenzoxy-(Cbz))-amino-ethyl-N-(1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluor tridecyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide

Under 0 ℃, 7.42g (36.59mmol) dicyclohexylcarbodiimide is added into the title compound of embodiment 11b of 20g (29.22mmol) and 6.49g (29.22mmol) { 2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-acetate (people such as Voegtle, LiebigsAnn.Chem., 1980,858-862) with the solution of 3.29g (29.22mmol) N-maloyl imines in the 200ml dimethyl formamide in, stirred 3 hours down at 0 ℃, at room temperature stirred then 16 hours.The sedimentary urea of institute is leached, in a vacuum filtrate is evaporated to drying regime, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 20.3g (theoretical amount 78%).

Ultimate analysis:

Calculated value: C 41.90 H 4.20 N 3.15 F 36.35

Measured value: C 42.16 H 4.28 N 3.12 F 36.21

D) N-(2-amino-ethyl)-N-(1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa--perfluor tridecyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, mesylate

2.06g (21.38mmol) methylsulfonic acid and 3.0g palladium catalyst (10% Pd/C) are added in the solution of title compound in 300ml ethanol of embodiment 11c of 19.0g (21.38mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 18.2g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 33.89 H 4.15 N 3.29 F 37.97

Measured value: C 34.11 H 4.21 N 3.10 F 37.69

E) N-{[1,4,7-three-(carboxymethyl)-1; 4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H; 1H; 2H, 2H, 4H; 4H; 5H, 5H-3-oxa--perfluor tridecyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Gd complex compound

Under mild heat, title compound, 2.14g (18.55mmol) N-maloyl imines, 1.57g (37.10mmol) lithium chloride and 11.68g (18.55mmol) 1 with the embodiment 11d of 15.8g (18.55mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Add 4.78g (23.19mmol) dicyclohexylcarbodiimide and 1.88g (18.55mmol) triethylamine down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 19.8g (theoretical amount 73%) colorless solid

Water content (Karl-Fischer): 6.5%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.92 H 4.35 N 7.18 F 23.64 Gd 11.51

Measured value: C 37.15 H 4.30 N 7.07 F 23.51 Gd 11.44

Embodiment 12

A) N-[2-(carbobenzoxy-(Cbz))-amino-ethyl-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-(2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group-oxyethyl group)-ethanamide

Under 0 ℃, 8.05g (39.04mmol) dicyclohexylcarbodiimide is added into the title compound of embodiment 1a of 20g (31.23mmol) and 8.32g (31.23mmol) (2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group-oxyethyl group)-acetate (people such as Voegtle, Liebigs Ann.Chem., 1980,858-862) with the solution of 3.59g (31.23mmol) N-maloyl imines in the 200ml dimethyl formamide in, stirred 3 hours down at 0 ℃, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 22.1g (theoretical amount 80%).

Ultimate analysis:

Calculated value: C 41.90 H 4.20 N 3.15 F 36.35

Measured value: C 42.14 H 4.26 N 3.11 F 36.12

B) N-(2-amino-ethyl)-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, mesylate

2.28g (23.63mmol) methylsulfonic acid and 4.0g palladium catalyst (10% Pd/C) are added in the solution of title compound in 500ml ethanol of embodiment 12a of 21g (23.63mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 20.1g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 33.89 H 4.15 N 3.29 F 37.97

Measured value: C 34.08 H 4.19 N 3.17 F 37.65

C) N-{[1; 4; 7-three-(carboxymethyl)-1; 4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H; 1H; 2H, 2H-perfluor decyl)-2-(2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-oxyethyl group)-ethanamide, the Gd complex compound

Under mild heat, title compound, 2.29g (19.88mmol) N-maloyl imines, 1.68g (39.76mmol) lithium chloride and 12.52g (19.88mmol) 1 with the embodiment 12b of 16.9g (19.88mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Add 5.13g (24.85mmol) dicyclohexylcarbodiimide and 2.01g (19.88mmol) triethylamine down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 18.1g (theoretical amount 62%) colorless solid

Water content (Karl-Fischer): 6.8%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.92 H 4.35 N 7.18 F 23.64 Gd 11.51

Measured value: C 37.11 H 4.38 N 7.09 F 23.51 Gd 11.44

Embodiment 13

A) N-[2-(carbobenzoxy-(Cbz))-amino-ethyl-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-methoxyl group ethanamide

Under 0 ℃, 8.05g (39.04mmol) dicyclohexylcarbodiimide is added in the title compound of embodiment 1a of 20g (31.23mmol) and 2.81g (31.23mmol) 2-methoxyacetic acid (Aldrich) and the solution of 3.59g (31.23mmol) N-maloyl imines in the 200ml dimethyl formamide, stirred 3 hours down at 0 ℃, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 17.1g (theoretical amount 77%).

Ultimate analysis:

Calculated value: C 38.78 H 2.97 N 3.93 F 45.34

Measured value: C 38.94 H 3.01 N 3.88 F 45.22

B) N-(2-amino-ethyl)-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-methoxyl group ethanamide, mesylate

2.23g (23.16mmol) methylsulfonic acid and 4.0g palladium catalyst (10% Pd/C) are added in the solution of title compound in 500ml ethanol of embodiment 13a of 16.5g (23.16mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 15.1g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 28.50 H 2.84 N 4.15 F 47.89

Measured value: C 28.79 H 2.96 N 4.09 F 47.53

C) N-{[1,4,7-three-(carboxymethyl)-1,4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-methoxyl group ethanamide, the Gd complex compound

Under mild heat, title compound, 1.99g (17.29mmol) N-maloyl imines, 1.46g (34.58mmol) lithium chloride and 10.89g (17.29mmol) 1 with the embodiment 13b of 11.7g (17.29mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WOHH98/24775, Schering AG (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Add 4.46g (21.6mmol) dicyclohexylcarbodiimide and 1.75g (17.29mmol) triethylamine down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 12.9g (theoretical amount 59%) colorless solid

Water content (Karl-Fischer): 6.0%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 34.32 H 3.64 N 8.24 F 27.14 Gd 13.21

Measured value: C 34.59 H 3.69 N 8.18 F 26.98 Gd 13.14

Embodiment 14

A) N-[2-(carbobenzoxy-(Cbz))-amino-ethyl-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide

Under 0 ℃, 8.05g (39.04mmol) dicyclohexylcarbodiimide is added into the title compound of embodiment 1a of 20g (31.23mmol) and 6.94g (31.23mmol) { 2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-acetate (people such as Voegtle, Liebigs Ann.Chem., 1980,858-862) with the solution of 3.59g (31.23mmol) N-maloyl imines in the 200ml dimethyl formamide in, stirred 3 hours down at 0 ℃, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 22.3g (theoretical amount 85%).

Ultimate analysis:

Calculated value: C 41.24 H 3.94 N 3.32 F 38.24

Measured value: C 41.37 H 3.99 N 3.27 F 38.11

2.40g (24.86mmol) methylsulfonic acid and 4.0g palladium catalyst (10% Pd/C) are added in the solution of title compound in 500ml ethanol of embodiment 14a of 21g (24.86mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 20.1g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 32.76 H 3.87 N 3.47 F 40.04

Measured value: C 32.88 H 3.91 N 3.33 F 39.89

C) N-{[1; 4; 7-three-(carboxymethyl)-1; 4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H; 1H; 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Gd complex compound

Under mild heat, title compound, 1.62g (14.08mmol) N-maloyl imines, 1.19g (28.12mmol) lithium chloride and 8.87g (14.08mmol) 1 with the embodiment 14b of 11.4g (14.08mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Add 3.63g (17.6mmol) dicyclohexylcarbodiimide and 1.43g (14.08mmol) triethylamine down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 13.9g (theoretical amount 71%) colorless solid

Water content (Karl-Fischer): 5.7%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.34 H 4.19 N 7.42 F 24.43 Gd 11.89

Measured value: C 36.57 H 4.22 N 7.44 F 24.29 Gd 11.77

Embodiment 15

A) N-[2-(carbobenzoxy-(Cbz))-amino-ethyl-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-(2-methoxy ethoxy)-ethanamide

Under 0 ℃, 8.05g (39.04mmol) dicyclohexylcarbodiimide is added in the title compound of embodiment 1a of 20g (31.23mmol) and 4.19g (31.23mmol) (2-methoxy ethoxy)-acetate (Aldrich) and the solution of 3.59g (31.23mmol) N-maloyl imines in the 200ml dimethyl formamide, stirred 3 hours down at 0 ℃, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 17.5g (theoretical amount 74%).

Ultimate analysis:

Calculated value: C 39.70 H 3.33 N 3.70 F 42.70

Measured value: C 40.01 H 3.42 N 3.66 F 42.54

B) N-(2-amino-ethyl)-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-(2-methoxy ethoxy)-ethanamide, mesylate

2.17g (22.47mmol) methylsulfonic acid and 3.0g palladium catalyst (10% Pd/C) are added in the solution of title compound in 500ml ethanol of embodiment 15a of 17g (22.47mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 16.2g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 30.09 H 3.23 N 3.90 F 44.96

Measured value: C 30.33 H 3.25 N 3.84 F 44.77

C) N-{[1,4,7-three-(carboxymethyl)-1,4; 7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H, 1H; 2H, 2H-perfluor decyl)-2-(2-methoxy ethoxy)-ethanamide, the Gd complex compound

Under mild heat, title compound, 1.85g (16.07mmol) N-maloyl imines, 1.36g (32.14mmol) lithium chloride and 10.12g (16.07mmol) 1 with the embodiment 15b of 11.5g (16.07mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Under 10 ℃, add 4.14g (20.08mmol) dicyclohexylcarbodiimide and 1.63 (16.07mmol) triethylamine, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 14.2g (theoretical amount 67%) colorless solid

Water content (Karl-Fischer): 6.0%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 35.04 H 3.84 N 7.95 F 26.17 Gd 12.74

Measured value: C 35.38 H 3.88 N 7.91 F 25.99 Gd 12.63

Embodiment 16

A) 1-N-(carbobenzoxy-(Cbz))-1H, 1H, 2H, 2H, 3H, 3H, 4H, 4H, 6H, 6H-4-azepine-perfluor tetradecy lamine

N-carbobenzoxy-(Cbz)-propylene diamine (people such as Atwell with 25.0g (120mmol), Synthesis, 1984,1032-1033) and the triethylamine of 10.2g (100mmol) be added into 500 milliliters of 54.22g (100mmol) methylsulfonic acid-(1H, 1H in the acetonitrile, 2H, 2H-perfluor decyl)-ester (people such as Bartsch, Tetrahedron, 2000,3291-3302), and under 60 ℃, stirred 48 hours.Indissolvable component is leached from reaction soln, in a vacuum it is evaporated to drying regime, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless wax of output: 40.7g (theoretical amount 62%)

Ultimate analysis:

Calculated value: C 38.55 H 2.93 N 4.28 F 49.36

Measured value: C 38.73 H 2.89 N 4.17 F 49.11

B) N-[3-(carbobenzoxy-(Cbz))-aminopropyl-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide

Under 0 ℃, 7.99g (38.74mmol) dicyclohexylcarbodiimide is added into the title compound of embodiment 16a of 20g (30.99mmol) and 6.89g (30.99mmol) { 2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-acetate (people such as Voegtle, LiebigsAnn.Chem., 1980,858-862) with the solution of 3.56g (30.99mmol) N-maloyl imines in the 200ml dimethyl formamide in, stirred 3 hours down at 0 ℃, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 21.5g (theoretical amount 81%).

Ultimate analysis:

Calculated value: C 41.97 H 4.11 N 3.26 F 37.62

Measured value: C 42.24 H 4.18 N 3.15 F 37.44

C) N-(3-aminopropyl)-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, mesylate

2.25g (23.29mmol) methylsulfonic acid and 4.0g palladium catalyst (10% Pd/C) are added in the solution of title compound in 500ml ethanol of embodiment 16b of 20g (23.29mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 19.2g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 33.67 H 4.05 N 3.41 F 39.36

Measured value: C 33.94 H 4.09 N 3.27 F 39.11

D) N-{[1; 4; 7-three-(carboxymethyl)-1; 4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 3-aminopropyl }-N-(1H; 1H; 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Gd complex compound

Under mild heat, title compound, 1.59g (13.80mmol) N-maloyl imines, 1.17g (27.60mmol) lithium chloride and 8.79g (13.80mmol) 1 with the embodiment 16c of 11.3g (13.80mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Add 3.59g (17.4mmol) dicyclohexylcarbodiimide and 1.40g (13.80mmol) triethylamine down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 12.9g (theoretical amount 66%) colorless solid

Water content (Karl-Fischer): 6.0%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.86 H 4.30 N 7.34 F 24.17 Gd 11.77

Measured value: C 36.99 H 4.37 N 7.31 F 24.01 Gd 11.69

Embodiment 17

A) 1-N-(carbobenzoxy-(Cbz))-1H, 1H, 2H, 2H, 3H, 3H, 4H, 4H, 6H, 6H, 7H, 7H-5-azepine-perfluor pentadecyl amine

N-carbobenzoxy-(Cbz)-butanediamine (people such as Atwell with 26.67g (120mmol), Synthesis, 1984,1032-1033) and 10.2g (100mmol) triethylamine be added into 500 milliliters of 54.22g (100mmol) methylsulfonic acid-(1H, 1H in the acetonitrile, 2H, 2H-perfluor decyl)-ester (people such as Bartsch, Tetrahedron, 2000,3291-3302), and under 60 ℃, stirred 48 hours.Indissolvable component is leached from reaction soln, in a vacuum it is evaporated to drying regime, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless wax of output: 39.6g (theoretical amount 59%)

Ultimate analysis:

Calculated value: C 39.53 H 3.17 N 4.19 F 48.32

Measured value: C 39.74 H 3.21 N 4.17 F 48.17

B) N-[4-(carbobenzoxy-(Cbz))-amino butyl-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide

Under 0 ℃, 7.71g (37.4mmol) dicyclohexylcarbodiimide is added into the title compound of embodiment 17a of 20g (29.92mmol) and 6.65g (29.92mmol) { 2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-acetate (people such as Voegtle, LiebigsAnn.Chem., 1980,858-862) with the solution of 3.44g (29.92mmol) N-maloyl imines in the 200ml dimethyl formamide in, stirred 3 hours down at 0 ℃, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 26.0g (theoretical amount 79%).

Ultimate analysis:

Calculated value: C 42.67 H 4.27 N 3.21 F 37.01

Measured value: C 42.85 H 4.30 N 3.16 F 36.87

C) N-(the amino butyl of 4-)-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide

4.0g palladium catalyst (10% Pd/C) is added in the solution of title compound in 500ml ethanol of embodiment 17b of 20g (22.92mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 17.0g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 37.41 H 4.23 N 3.79 F 43.73

Measured value: C 37.59 H 4.29 N 3.74 F 43.61

D) N-{[1; 4; 7-three-(carboxymethyl)-1; 4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the amino butyl of 4-}-N-(1H; 1H; 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Gd complex compound

Under mild heat, title compound, 1.56g (13.54mmol) N-maloyl imines, 1.14g (26.08mmol) lithium chloride and 8.69g (13.54mmol) 1 with the embodiment 17c of 10g (13.54mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Under 10 ℃, add 3.53g (17.07mmol) dicyclohexylcarbodiimide, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 11.7g (theoretical amount 60%) colorless solid

Water content (Karl-Fischer): 6.5%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 37.36 H 4.40 N 7.26 F 23.92 Gd 11.65

Measured value: C 37.51 H 4.44 N 7.22 F 23.84 Gd 11.59

Embodiment 18

A) N-[2-(carbobenzoxy-(Cbz))-amino-ethyl-N-(1H, 1H, 2H, 2H, 4H, 4H-3-oxa-perfluor dodecyl)-2-[2-(2-methoxy ethoxy)-oxyethyl group]-ethanamide

Under 0 ℃, 7.69g (37.29mmol) dicyclohexylcarbodiimide is added in the title compound of embodiment 10c of 20g (29.83mmol) and 5.32g (29.83mmol) [2-(2-methoxy ethoxy)-oxyethyl group]-acetate (Aldrich) and the solution of 3.43g (29.83mmol) N-maloyl imines in the 200ml dimethyl formamide, and under 0 ℃, stirred 3 hours, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 17.9g (theoretical amount 72%).

Ultimate analysis:

Calculated value: C 40.49 H 3.76 N 3.37 F 38.89

Measured value: C 40.62 H 3.81 N 3.38 F 38.77

B) N-(2-amino-ethyl)-N-(1H, 1H, 2H, 2H, 4H, 4H-3-oxa--perfluor dodecyl)-2-[2-(2-methoxy ethoxy)-oxyethyl group]-ethanamide, mesylate

1.98g (20.50mmol) methylsulfonic acid and 3.0g palladium catalyst (10% Pd/C) are added in the solution of title compound in 300ml ethanol of embodiment 18c of 17.0g (20.50mmol), and hydrogenation at room temperature 24 hours.Catalyzer is leached, and in a vacuum filtrate is evaporated to drying regime.

Output: 16.3g (quantitative) colorless solid.

Ultimate analysis:

Calculated value: C 31.83 H 3.69 N 3.53 F 40.75

Measured value: C 31.57 H 3.78 N 3.44 F 40.51

C) N-{[1; 4,7-three-(carboxymethyl)-1,4; 7; 10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H, 1H, 2H; 2H; 4H, 4H-3-oxa--perfluor dodecyl)-2-[2-(2-methoxy ethoxy)-oxyethyl group]-ethanamide, the Gd complex compound

Under mild heat, title compound, 2.11g (18.30mmol) N-maloyl imines, 1.55g (36.60mmol) lithium chloride and 11.52g (18.30mmol) 1 with the embodiment 18d of 14.75g (18.30mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, Schering AG (embodiment 1)) is dissolved in the 200ml methyl-sulphoxide.Under 10 ℃, add 4.72g (22.88mmol) dicyclohexylcarbodiimide and 1.85g (18.30mmol) triethylamine, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 17.6g (theoretical amount 69%) colorless solid

Water content (Karl-Fischer): 6.1%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 35.81 H 4.06 N 7.50 F 24.69 Gd 12.02

Measured value: C 36.04 H 4.11 N 7.49 F 24.52 Gd 11.94

Embodiment 19

A) 1-N-(tertbutyloxycarbonyl)-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H, 7H, 7H, 8H, 8H-6-azepine-3-oxa-perfluor cetylamine

With 6.13g (30mmol) N-tertbutyloxycarbonyl-3-oxa--pentamethylene diamine (people such as Koenig, Eur.J.Org.Chem., 2002,3004-3014) and 2.55g (25mmol) triethylamine be added into 150 milliliters of 13.56g (25mmol) methylsulfonic acid-(1H, 1H in the acetonitrile, 2H, 2H-perfluor decyl)-ester (people such as Bartsch, Tetrahedron, 2000,3291-3302), and at 60 ℃ stirred 48 hours down.Indissolvable component is leached from reaction soln, in a vacuum it is evaporated to drying regime, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless wax of output: 10.9g (theoretical amount 67%)

Ultimate analysis:

Calculated value: C 35.09 H 3.56 N 4.31 F 49.66

Measured value: C 35.28 H 3.64 N 4.24 F 49.53

B) N-[5-(tertbutyloxycarbonyl)-amino-3-oxa-amyl group-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-{-2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide

Under 0 ℃, 3.97g (19.23mmol) dicyclohexylcarbodiimide is added into the title compound of embodiment 19a of 10g (15.38mmol) and 3.42g (15.38mmol) { 2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-acetate (people such as Voegtle, LiebigsAnn.Chem., 1980,858-862) with the solution of 1.77g (15.38mmol) N-maloyl imines in the 200ml dimethyl formamide in, stirred 3 hours down at 0 ℃, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 9.9g (theoretical amount 75%).

Ultimate analysis:

Calculated value: C 39.35 H 4.60 N 3.28 F 37.79

Measured value: C 39.57 H 4.66 N 3.16 F 36.55

C) N-(5-amino-3-oxa-amyl group)-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide

Under 0 ℃, the 50ml trifluoroacetic acid is added in the solution of title compound in the 100ml methylene dichloride of embodiment 19b of 9.5g (11.12mmol), and at room temperature stirred 3 hours.Vacuum-evaporation is to drying regime, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 10: 1).

Output: 7.8g (theoretical amount 93%) colorless solid

Ultimate analysis:

Calculated value: C 36.62 H 4.14 N 3.71 F 42.81

Measured value: C 36.88 H 4.21 N 3.55 F 43.25

D) N-{[1; 4; 7-three-(carboxymethyl)-1; 4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-5-amino-3-oxa-amyl group }-N-(1H; 1H; 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Gd complex compound

Under mild heat, title compound, 1.07g (9.28mmol) N-maloyl imines, 787mg (18.56mmol) lithium chloride and 5.84g (9.28mmol) 1 with the embodiment 19c of 7g (9.28mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, ScheringAG (embodiment 1)) is dissolved in the 100ml methyl-sulphoxide.Under 10 ℃, add 2.39g (11.6mmol) dicyclohexylcarbodiimide, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 8.8g (theoretical amount 65%) colorless solid

Water content (Karl-Fischer): 6.5%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.92 H 4.35 N 7.18 F 23.64 Gd 11.51

Measured value: C 37.04 H 4.39 N 7.15 F 23.57 Gd 11.47

Embodiment 20

A) 1-N-(tertbutyloxycarbonyl)-1H, 1H, 2H, 3H, 4H, 4H, 6H, 6H, 7H, 7H-5-azepine-[2,3-(2,2-dimethyl-[1,3]-dioxolanyl)]-perfluor pentadecyl amine

With 7.81g (30mmol) N-tertbutyloxycarbonyl-[2,3-(2,2-dimethyl-[1,3]-dioxolanyl)] butanediamine is [with the preparation that is similar to N-tertbutyloxycarbonyl-3-oxa--pentamethylene diamine from (5-amino-ethyl-2,2-dimethyl-[1,3]-dioxolane-4-yl)-methylamine (ACROS) preparation (people such as Koenig, Eur.J.Org.Chem., 2002,3004-3014)] and 2.55g (25mmol) triethylamine be added into 13.56g (25mmol) methylsulfonic acid-(1H in the 150ml acetonitrile, 1H, 2H, 2H-perfluor decyl)-ester (people such as Bartsch, Tetrahedron, 2000,3291-3302), and under 60 ℃, stirred 48 hours.Indissolvable component is leached from reaction soln, in a vacuum it is evaporated to drying regime, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless wax of output: 12.5g (theoretical amount 71%)

Ultimate analysis:

Calculated value: C 37.40 H 3.85 N 3.97 F 45.72

Measured value: C 37.66 H 3.94 N 3.88 F 45.61

B) N-{4-(tertbutyloxycarbonyl)-amino-[2,3-(2,2-dimethyl-[1,3]-dioxolanyl)]-butyl }-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-{-2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide

Under 0 ℃, 3.65g (17.7mmol) dicyclohexylcarbodiimide is added into the title compound of embodiment 20a of 10g (14.16mmol) and 3.15g (14.16mmol) { 2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-acetate (people such as Voegtle, LiebigsAnn.Chem., 1980,858-862) with the solution of 1.63g (14.16mmol) N-maloyl imines in the 200ml dimethyl formamide in, stirred 3 hours down at 0 ℃, at room temperature stirred then 16 hours.To precipitate urea and leach, in a vacuum filtrate will be evaporated to drying regime, and residue will be carried out silica gel chromatography (mobile solvent: methylene chloride 20: 1).

The colourless heavy-gravity oily matter of output: 8.9g (theoretical amount 69%).

Ultimate analysis:

Calculated value: C 40.89 H 4.76 N 3.08 F 35.47

Measured value: C 40.97 H 4.85 N 3.00 F 35.37

C) N-(4-amino-2,3-dihydroxyl butyl)-N-(1H, 1H, 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide

Under 0 ℃, the 50ml trifluoroacetic acid is added in the solution of title compound in the 100ml methylene dichloride of embodiment 20b of 8.2g (9.00mmol), and at room temperature stirred 3 hours.Be evaporated to drying regime in a vacuum, and residue is carried out silica gel chromatography (mobile solvent: methylene chloride 10: 1 to 2: 1).

Output: 6.68g (theoretical amount 96%) colorless solid

Ultimate analysis:

Calculated value: C 35.85 H 4.06 N 3.64 F 41.92

Measured value: C 36.05 H 4.11 N 3.60 F 41.77

D) N-{[1; 4; 7-three-(carboxymethyl)-1,4,7; 10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-(4-amino-2; 3-dihydroxyl butyl)-N-(1H, 1H, 2H; 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Gd complex compound

Under mild heat, title compound, 897mg (7.79mmol) N-maloyl imines, 660mg (15.58mmol) lithium chloride and 4.90g (7.79mmol) 1 with the embodiment 20c of 6g (7.79mmol), 4,7-three-(carboxymethyl)-10-[1-carboxyl-3-azepine-4-oxo-5-methylpent-5-yl]-1,4,7, the 10-tetraazacyclododecanand, Gd complex compound (WO 98/24775, ScheringAG (embodiment 1)) is dissolved in the 100ml methyl-sulphoxide.Add 2.01g (9.74mmol) dicyclohexylcarbodiimide down at 10 ℃, and at room temperature stirred 16 hours.Pour into solution in the 2000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 6.9g (theoretical amount 59%) colorless solid

Water content (Karl-Fischer): 7.7%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.50 H 4.30 N 7.09 F 23.37 Gd 11.38

Measured value: C 36.71 H 4.35 N 7.02 F 23.41 Gd 11.29

Embodiment 21

A) N-{[1; 4; 7-three-(carboxymethyl)-1,4,7; 10-tetraazacyclododecanand-10-N-(butyryl radicals-4-(R)-carboxylic-4-yl)]-the 2-amino-ethyl }-N-(1H; 1H, 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide; Gd complex compound list sodium salt and N-({ 1; 4,7-three-(carboxymethyl)-1,4; 7; 10-tetraazacyclododecanand-10-N-(ethano--[2-(R)-carboxy ethyl]-yl) }-the 2-amino-ethyl }-N-(1H, 1H, 2H; 2H-perfluor decyl)-2-{-2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, Gd complex compound list sodium salt

Title compound, 448mg (4.4mmol) triethylamine and 3.51g (4.4mmol) 2-(R)-2-[4 with the embodiment 14b of 2.84g (3.52mmol), 7,10-three-(carboxymethyl)-1,4,7,10-tetraazacyclododecanand-1-yl] pentane dicarboxylic acid list pentafluorophenyl esters, Gd complex compound (WO2005/0014154, EPIX PHARMACEUTICALS, INC., (embodiment 9:EP-2104-15-Pfp)) be dissolved in the 50ml methyl-sulphoxide, mix with 356mg (3.52mmol) triethylamine, and at room temperature stirred 16 hours.Solution is poured in the 1000ml acetone, and stirred in addition 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.The part that will contain product is dissolved in the water by evaporation concentration, with the neutralization of 0.1N sodium hydroxide solution, freeze-drying then.

Output: 2.03g (theoretical amount 39%) colorless solid is 3: 2 a regional isomerism mixture.

Water content (Karl-Fischer): 9.2%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 35.72 H 3.97 N 6.25 F 24.01 Gd 11.69

Measured value: C 36.01 H 4.06 N 6.29 F 23.89 Gd 11.46

Embodiment 22

A) N-{[1; 4; 7-three-(carboxymethyl)-1,4,7; 10-tetraazacyclododecanand-10-N-(butyryl radicals-4-(R)-carboxylic-4-yl)]-the 2-amino-ethyl }-N-(1H; 1H, 2H, 2H-perfluor decyl)-2-(1-O-alpha-d-galactopy mannose group)-ethanamide; Gd complex compound list sodium salt and N-({ 1; 4,7-three-(carboxymethyl)-1,4; 7; 10-tetraazacyclododecanand-10-N-(ethano--[2-(R)-carboxy ethyl]-yl) }-the 2-amino-ethyl)-N-(1H, 1H, 2H; 2H-perfluor decyl)-and 2-(1-O-alpha-d-galactopy mannose group)-ethanamide, Gd complex compound list sodium salt

Title compound, 436mg (4.3mmol) triethylamine and 3.43g (4.3mmol) 2-(R)-2-[4 with the embodiment 1c of 2.83g (3.44mmol), 7,10-three-(carboxymethyl)-1,4,7,10-tetraazacyclododecanand-1-yl] pentane dicarboxylic acid list pentafluorophenyl esters, Gd complex compound (WO2005/0014154, EPIX PHARMACEUTICALS, INC., (embodiment 9:EP-2104-15Pfp)) be dissolved in the 50ml methyl-sulphoxide, mix with 348mg (3.44mmol) triethylamine, and at room temperature stirred 16 hours.Pour into solution in the 1000ml acetone and stirred other 10 minutes.Precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.The part that will contain product is dissolved in the water by evaporation concentration, with the neutralization of 0.1N sodium hydroxide solution, freeze-drying then.

Output: 1.64g (theoretical amount 32%) colorless solid is 3: 2 a regional isomerism mixture.

Water content (Karl-Fischer): 8.8%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 34.42 H 3.63 N 6.17 F 23.73 Gd 11.55

Measured value: C 34.66 H 3.60 N 6.09 F 23.78 Gd 11.39

Embodiment 23

A) N-{[1; 4; 7-three-(carboxymethyl)-1; 4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl } N-(1H; 1H; 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, trisodium salt

The title compound of the embodiment 14c of 10g (7.13mmol) is dissolved in the mixture of being made up of 100ml water and 30ml Virahol, mixes with 2.25g (24.96mmol) oxalic acid, and be heated to 100 ℃ through 5 hours.After being cooled to room temperature, precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.The part that will contain product is dissolved in the water by evaporation concentration, is 10 with the 0.1N sodium hydroxide solution with pH regulator, freeze-drying then.

Output: 7.39g (theoretical amount 77%) colorless solid

Water content (Karl-Fischer): 8.2%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 38.94 H 4.49 N 7.95 F 26.18

Measured value: C 39.03 H 4.44 N 7.98 F 25.89

B) N-{[1; 4; 7-three-(carboxymethyl)-1; 4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H; 1H; 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Dy complex compound

The title compound of the embodiment 23a of 2.0g (1.49mmol) is dissolved in 50ml water and the 1ml acetate, mixes, and stirred 6 hours down at 80 ℃ with 441mg (1.64mmol) Dysprosium trichloride.With the ammonia neutralization, be evaporated to drying regime, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 1.78g (theoretical amount 84%) colorless solid

Water content (Karl-Fischer): 6.2%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.19 H 4.18 N 7.39 F 24.33 Dy 12.24

Measured value: C 36.32 H 4.24 N 7.30 F 24.19 Dy 12.16

Embodiment 24

A) N-{[1; 4; 7-three-(carboxymethyl)-1; 4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl }-N-(1H; 1H; 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Yb complex compound

The title compound of the embodiment 23a of 2.0g (1.49mmol) is dissolved in 50ml water and the 1ml acetate, mixes, and stirred 6 hours down at 80 ℃ with 458mg (1.64mmol) Ytterbium trichloride.With ammonia it is neutralized, be evaporated to drying regime, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 1.84g (theoretical amount 86%) colorless solid

Water content (Karl-Fischer): 6.9%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 35.91 H 4.14 N 7.33 F 24.14 Yb 12.93

Measured value: C 36.05 H 4.19 N 7.31 F 24.00 Yb 12.79

Embodiment 25

A) N-{[1; 4; 7-three-(carboxymethyl)-1; 4,7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-the 2-amino-ethyl } N-(1H; 1H; 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Y-complex compound

The title compound of the embodiment 23a of 2.0g (1.49mmol) is dissolved in 50ml water and the 1ml acetate, mixes, and stirred 6 hours down at 80 ℃ with 320mg (1.64mmol) Yttrium trichloride.With the ammonia neutralization, be evaporated to drying regime, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 1.56g (theoretical amount 79%) colorless solid

Water content (Karl-Fischer): 5.5%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 38.32 H 4.42 N 7.82 F 25.76 Y 7.09

Measured value: C 38.56 H 4.51 N 7.88 F 25.65 Y 6.98

Embodiment 26

A) 10-(5-oxo-tetrahydrofuran (THF)-2-ylmethyl)-1,4,7-three (carboxymethyl)-1,4,7,10-tetraazacyclododecanand

8.3g (207.6mmol) sodium hydroxide is added into 12.0g (34.6mmol) 1,4 in the 50ml water, and 7-three (carboxymethyl)-1,4,7 is in the 10-tetraazacyclododecanand (D03A).To wherein dropwise adding because 5.02g (43.25mmol) the 3-Oxyranyle propionic acid in 50ml propyl carbinol/50ml 2-propyl alcohol (people such as Dakoji, J.Am.Chem.Soc., 1996, the 10971-10979) solution of Zu Chenging, and solution was heated to 80 ℃ through 24 hours.In a vacuum reaction soln is evaporated to drying regime, residue is mixed with 300 ml waters, and be 3 with pH regulator with 3N hydrochloric acid.Then,, in a vacuum the butanols that merges is evaporated to drying regime mutually with each 200ml n-butanol extraction three times, and with residue by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 13.6g (theoretical amount 79%) colorless solid

Water content (Karl-Fischer): 10.4%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 51.34 H 7.26 N 12.60

Measured value: C 51.63 H 7.05 N 12.44

B) 10-(5-oxo-tetrahydrofuran (THF)-2-ylmethyl)-1,4,7-three (carboxymethyl)-1,4,7,10-tetraazacyclododecanand, Gd complex compound

The title compound of the embodiment 26a of 12.0g (24.2mmol) is dissolved in 100ml water and the 1ml acetate, mixes, and stirred 6 hours down at 80 ℃ with 4.39g (12.1mmol) gadolinium sesquioxide.Solution is filtered, be evaporated to drying regime, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 13.8g (theoretical amount 89%) colorless solid

Water content (Karl-Fischer): 6.5%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 38.12 H 4.88 N 9.36 Gd 26.26

Measured value: C 38.26 H 4.89 N 9.21 Gd 26.09

C) N-{[1,4,7-three-(carboxymethyl)-1,4; 7,10-tetraazacyclododecanand-10-N-(pentanoyl-4-hydroxyl-5-yl)]-the 2-amino-ethyl }-N-(1H, 1H; 2H, 2H-perfluor decyl)-2-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Gd complex compound

The title compound of the embodiment 26b of the title compound of the embodiment 14b of 2.84g (3.52mmol) and 3.38g (5.28mmol) is dissolved in the 50ml methyl alcohol, mixes with 356mg (3.52mmol) triethylamine, and under 50 ℃ temperature, stirred 48 hours.Be evaporated to drying regime, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 3.27g (theoretical amount 66%) colorless solid

Water content (Karl-Fischer): 6.9%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.70 H 4.31 N 6.42 F 24.67 Gd 12.01

Measured value: C 36.77 H 4.38 N 6.33 F 24.59 Gd 11.96

Embodiment 27

A) 1H, 1H, 2H; 2H, 4H, 4H; 5H; 5H-3-N-[1,4,7-three-(carboxymethyl)-1; 4; 7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-perfluor tridecyl-N-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Gd complex compound

Under 0 ℃, 2.58g (12.5mmol) dicyclohexylcarbodiimide and 1.01g (10mmol) triethylamine are added into the title compound of embodiment 2b of 12.14g (10mmol) and 2.22g (10mmol) { 2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-acetate (people such as Voegtle, Liebigs Ann.Chem., 1980,858-862) with the solution of 1.15g (10mmol) N-maloyl imines in the 100ml dimethyl formamide in, stirred 3 hours down at 0 ℃, at room temperature stirred then 16 hours.To precipitate urea and leach, and in a vacuum filtrate will be evaporated to drying regime.Residue is absorbed with less water, indissolvable component is leached, then filtrate is passed through chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 8.2g (theoretical amount 58%) colorless solid

Water content (Karl-Fischer): 6.2%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 36.34 H 4.19 N 7.42 F 24.43 Gd 11.89

Measured value: C 36.55 H 4.27 N 7.33 F 24.21 Gd 11.70

Embodiment 28

A) 1H, 1H, 2H; 2H, 4H, 4H; 5H; 5H-3-N-[1,4,7-three-(carboxymethyl)-1; 4; 7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-perfluor tridecyl-N-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, trisodium salt

The title compound of the embodiment 27a of 10g (7.11mmol) is dissolved in the mixture of being made up of 100ml water and 30ml Virahol, mixes with 2.25g (24.96mmol) oxalic acid, and be heated to 100 ℃ through 5 hours.After being cooled to room temperature, precipitated solid is leached, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.The part that will contain product is dissolved in water by evaporation concentration, is 8 with the 0.1N sodium hydroxide solution with pH regulator, freeze-drying then.

Output: 8.64g (theoretical amount 91%) colorless solid

Water content (Karl-Fischer): 7.5%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 38.94 H 4.49 N 7.95 F 26.18

Measured value: C 38.88 H 4.40 N 7.65 F 25.77

B) 1H, 1H, 2H; 2H, 4H, 4H; 5H; 5H-3-N-[1,4,7-three-(carboxymethyl)-1; 4; 7,10-tetraazacyclododecanand-10-N-(pentanoyl-3-azepine-4-oxo-5-methyl-5-yl)]-perfluor tridecyl-N-{2-[2-(2-methoxy ethoxy)-oxyethyl group]-oxyethyl group }-ethanamide, the Y complex compound

The title compound of the embodiment 28a of 2.0g (1.50mmol) is dissolved in 50ml water and the 1ml acetate, mixes, and stirred 6 hours down at 80 ℃ with 320mg (1.64mmol) Yttrium trichloride.With the ammonia neutralization, be evaporated to drying regime, then by chromatogram (RP-18; Mobile solvent: the gradient of forming by water/acetonitrile) purifying.

Output: 1.43g (theoretical amount 72%) colorless solid

Water content (Karl-Fischer): 5.0%

Ultimate analysis (with respect to anhydrous substances):

Calculated value: C 38.32 H 4.42 N 7.82 F 25.76 Y 7.09

Measured value: C 38.48 H 4.55 N 7.75 F 25.66 Y 6.96

Embodiment 29: relaxivity

Under 40 ℃, T1 and T2 relaxation time when using NMR pulse wave spectrometer (Minispec PC 20) under 0.47T, to measure water and blood plasma along with the gadolinium complex concentration increase of the title substance of wherein contained embodiment 1d, 5c, 14c, 15c.The result is presented in the table 1.

Embodiment 30: the acute toxicity effect after the administration in the disposable vein in the mouse

(preliminary examination)

Gadolinium complex intravenous administration mouse (n=3 with the title substance of embodiment 1d, 5c, 14c, 15c; Injection rate: 2ml/min), the acute consistency (LD of rough determination whole body ₅₀).Under each situation, checked several dosage with 7 day observation period.The acute toxicity effect of expection is found in the table 1.

Embodiment 31: the drainage in the rat medium sized vein after the administration

With the gadolinium complex of the title substance of embodiment 1d, 5c, 14c, 15c with the total gadolinium of 50 μ mol/kg body weight intravenous administration rat (n=3) after, measure after the administration in the drainage medium of 14 days urine and excrement and the metal content of (body rest part) in the body by Atomic Emission SpectrometerAES (ICP-AES).The result is presented in the table 1.

Embodiment 32: the blood plasma kinetics in the rat medium sized vein after the administration

Behind the gadolinium complex intravenous administration rat (n=3) of the total gadolinium of 50 μ mol/kg body weight with the title substance of embodiment 1d, 5c, 14c, 15c, in different time points (p.i.8 hour to 24 hours) through conduit at the arteria carotis communis blood sample collection, measure metal content and be converted to the blood plasma value by Atomic Emission SpectrometerAES (ICP-AES) through conversion factor (0.625).Calculate the eliminating transformation period by special software (WinNonlin) by plasma concentration.The result is presented in the table 1.

Embodiment 33: have and give in the rabbit medium sized vein of VX2-tumour to show (MRT) nodus lymphoideus transferring rate kitchen range and primary tumor behind the contrast medium

The picture of Fig. 1 and Fig. 2 is presented at has the embodiment 1d that intramuscular is implanted (precontrast) before iliac lymph nodes develops in the rabbit of VX2 tumour and intravenous administration 50 μ mol Gd/kg body weight) title substance after until 24 hours MR image.T1-weighting FSE image show give contrast medium (p.i.15 to 60 minute) back early in the time point healthy lymph node tissue strong signal rise.The zone that no signal rises in the lymphoglandula is diagnosed as transfer, and is confirmed (the H/E dyeing of lymph node section) (Fig. 1) on histology.

Very in surprise, can be observed also after the administration that (Fig. 2) appears clearly strengthening in (periphery especially) immediately in the primary tumor.Time point (p.i.24 hour) after, this enhancing is also expanded to tumor center.

Embodiment 34: MRT shows arteriosclerosis plaque after giving contrast medium in the rat medium sized vein

The picture of Fig. 3 demonstrates, Watanabe rabbit (WHHL rabbit; Arteriosclerosis is brought out in heredity) and do not have the embodiment 1d that gives 50 μ mol Gd/kg body weight in control animal (New Zealand white rabbit (white New the Zealander)) medium sized vein of arteriosclerosis) and the title substance of embodiment 14c after 6 or 24 hours aortal MR images.T ₁-weighting inversion recovery image (IR-TFL, TR/TE/TI=300/4.0/120ms, 20 ° of α) shows that strong signal rises in the arteriosclerosis plaque of WHHL rabbit, then rises in the baseline image or in the vessel wall of normal healthy controls animal.Confirm the location of patch in aortic arch particularly and the blood vessel access by the Sudan-3 look.By this test, can demonstrate according to compound of the present invention and be suitable for the mark of making the artery plaque.

Embodiment 35: MRT shows inflammatory damage and necrotic area after giving contrast medium in the rat medium sized vein

By illustration, the picture of Fig. 4 shows, gives the MR image of struvite muscle injury in different time points place behind the title substance of embodiment 14c of 50 μ mol Gd/kg body weight and necrotic area in the rat medium sized vein.Inflammation/necrosis gives rose-red (20mg/kg by intravenously; Gave contrast medium preceding 24 hours) and brought out in 20 minutes by the xenon lamp irradiation subsequently.T ₁-weighting FSE image (1.5T; Sequence: T1-TSE; TR 451ms, TE 8.7ms) show that in the early stage strong signal rises in (until p.i.60 minute) inflammatory disorders tissue, and inhibit signal rising in the both central necrotic in the time of p.i.24 hour.

Embodiment 36: MRT shows lymphoglandula after giving contrast medium in the rat medium sized vein

By illustration, these pictures show, give the embodiment 5c of 50 μ mol Gd/kg body weight in the rat medium sized vein) title substance, embodiment 14c) title substance and embodiment 15c) title substance after the MR image of different time points place lymphoglandula.T ₁-weighting FSE image (1.5T; Sequence: T1-TSE; TR 451ms, TE 8.7ms) shows the rising of strong signal in the functional lymph node tissue of time point (until p.i.60 minute) in the early stage.

Table 1: about the physical chemistry and the experimental data of embodiment material

The numbering of the embodiment that compound is originated	Relaxivity [l/ (mmol*s)]	Body is detained 14 days [%]	The eliminating transformation period of blood	Gd content [%] in the p.i.24 hour blood	Mouse LD50 [mmol/kg]
The numbering of the embodiment that compound is originated	Relaxivity [l/ (mmol*s)]	Body is detained 14 days [%]	The eliminating transformation period of blood	Gd content [%] in the p.i.24 hour blood	Mouse LD50 [mmol/kg]	1	R1(w)：22.7 R1(p)：25.8 R2(w)：15.8 R2(p)：29.8	0.0％	4.8 hour	0.7％	＞10
5	R1(w)：18.9 R1(p)：24.8 R2(w)：23.9	0.0％	0.8 hour	0.0％		1	R1(w)：22.7 R1(p)：25.8 R2(w)：15.8 R2(p)：29.8	0.0％	4.8 hour	0.7％	＞10

The numbering of the embodiment that compound is originated	Relaxivity [l/ (mmol*s)]	Body is detained 14 days [%]	The eliminating transformation period of blood	Gd content [%] in the p.i.24 hour blood	Mouse LD50 [mmol/kg]
The numbering of the embodiment that compound is originated	Relaxivity [l/ (mmol*s)]	Body is detained 14 days [%]	The eliminating transformation period of blood	Gd content [%] in the p.i.24 hour blood	Mouse LD50 [mmol/kg]		R2(p)：32.8
14	R1(w)：18.6 R1(p)：25.5 R2(w)：21.6 R2(p)：33.5	0.0％	1.1 hour	0.0％	7.5		R2(p)：32.8
14	R1(w)：18.6 R1(p)：25.5 R2(w)：21.6 R2(p)：33.5	0.0％	1.1 hour	0.0％	7.5	15	R1(w)：17.2 R1(p)：24.6 R2(w)：15.1 R2(p)：33.2	0.0％	4.8 hour	0.2％	＞10

Relaxivity in R1 (w)=R1-water; Relaxivity in R1 (p)=R1 (w)=R1-blood plasma; Relaxivity in R2 (w)=R2-water; Relaxivity in R2 (p)=R1 (w)=R2-blood plasma.

Claims

1. the perfluoroalkyl-containing complexes with nitrogenous connection based structures of general formula I

Wherein

R represents

By the monose or the oligosaccharides group of 1-OH connection,

Q has the implication that is selected from following group in the case:

δ-CO-(CH ₂) _n″-ε

δ-NH-(CH ₂) _n″-ε

δ-(CH ₂) _m-ε

Wherein:

N " be 1 to 5 integer, and

M is 1 to 6 integer, and

Or

The complex compound K of general formula I I to V, wherein R ¹Herein for hydrogen atom or ordination number are 20-29,31-33,37-39,42-44,49 or the metal ion Equivalent of 57-83, and radicals R ², R ³, R ⁴, U and U ¹Has implication shown below;

Or

It can be straight or branched, saturated or undersaturated, and

Its

R wherein ⁷Be H or C ₁-C ₄Alkyl,

K represents the metal complex of general formula I I,

Wherein

Condition is at least two R ¹Expression metal ion Equivalent,

U represents optional by one or more Sauerstoffatoms, 1 to 3-NHCO group or 1 to 3-CONH group interruption and/or by 1 to 3-(CH ₂) _0-5The COOH group replaces-C ₆H ₄-O-CH ₂-ω-,-(CH ₂) _1-5-ω, phenylene ,-CH ₂-NHCO-CH ₂-CH (CH ₂COOH)-C ₆H ₄-ω-,-C ₆H ₄-(OCH ₂CH ₂) _0-1-N (CH ₂COOH)-CH ₂-ω or C ₁-C ₁₂-alkylidene group or-(CH ₂) _7-12-C ₆H ₄-O group, wherein ω represents and-connection site that CO-is connected;

Or the metal complex of general formula III

Or the metal complex of general formula I V

R wherein ¹With R ²Has above-mentioned implication;

Or the metal complex of general formula VA or VB

R wherein ¹Has above-mentioned implication;

Or the metal complex of general formula VI

R wherein ¹Has above-mentioned implication;

Or the metal complex of general formula VII

R wherein ¹And U ¹Have above-mentioned implication, wherein ω is and-connection site that CO-is connected,

Or the metal complex of general formula VIII

R wherein ¹Have above-mentioned implication,

And L represents to be selected from following group IXa) to IXc) group:

Wherein n ' and m ' represent the integer between 0 and 4 independently of each other, and m '+n ' 〉=1, and R ⁸With R ^{8 '}Be independently of each other-H or-OH, m '+n '＞1 wherein, each group-(CR ⁸R ^{8 '})-

Can be identical or different, and

W be direct key ,-O-maybe can choose the phenylene that is replaced by 1 to 4 hydroxyl wantonly, and q ' is 1,2,3 or 4,

Wherein α is the connection site that L is connected with complex compound K, and β is the connection site that L is connected with group Q, and γ represents the connection site that L is connected with radicals X,

And

The group of X expression (VI);

ρ—Y—(CH ₂) _s—(G) _t—(CH ₂) _s’—ζ

(X)

Wherein Y is direct key, group-CO-or group NR ⁶,

And its optional by 1-10 OH group, 1-5-COOH group, 1-2 individual-SO ₃H group, 1-5-NH ₂A group or 1-5 C ₁-C ₄Alkoxyl group replaces;

And G is-O-or-SO ₂-,

S and s ' they are 1 or 2 independently of each other, and t is 0 or 1, and

ρ represents the connection site that X is connected with L, and ξ represents X and R _fThe connection site that connects.

2. according to the metal complex of claim 1, it is characterized in that described metal ion Equivalent R ¹For ordination number is 21-29,39,42,44 or the element of 57-83.

3. according to the metal complex of claim 1, wherein said metal ion Equivalent R ¹For ordination number is 27,29,31-33,37-39,43,49,62,64,70,75 and 77 element.

4. according to the metal complex of one of claim 1 to 3 item, wherein R represents to have monose group or its deoxy compound of 5 to 6 C atoms, is preferably glucose, seminose or semi-lactosi.

5. according to the metal complex of one of claim 1 to 3 item, wherein R is selected from following group:

-C(O)CH ₂O[(CH ₂) ₂O] _pR′

-C(O)CH ₂OCH[CH ₂OCH(CH ₂OR′) ₂] ₂

-C(O)CH ₂OCH ₂CH[CH ₂OCH(CH ₂OR′) ₂] ₂

-R″N[(CH ₂) ₂O] _pR′

-N{[(CH ₂) ₂O] _pR′} ₂

-R″NCH ₂CH(OH)CH ₂OH

-N[CH ₂CH(OH)CH ₂OH] ₂

-R″NCH(CH ₂OH)CH(OH)CH ₂OH

-N[CH(CH ₂OH)CH(OH)CH ₂OH] ₂

-R″NCH[CH ₂OCH(CH ₂OR′) ₂] ₂

-R″NCH ₂CH[CH ₂OCH(CH ₂OR′) ₂] ₂

-R″NCH ₂CH ₂OCH[CH ₂OCH(CH ₂OR′) ₂] ₂

-R″NCH ₂CH ₂OCH ₂CH[CH ₂OCH(CH ₂OR′) ₂] ₂

-N{CH[CH ₂OCH(CH ₂OR′) ₂] ₂} ₂

-N{CH ₂CH[CH ₂OCH(CH ₂OR′) ₂] ₂} ₂

-R″NCH ₂CH(OH)CH(OH)CH(OH)CH(OH)CH ₂OH

-N[CH ₂CH(OH)CH(OH)CH(OH)CH(OH)CH ₂OH] ₂

And the complex compound of formula (II), wherein R ¹, R ², R ³With U as defined in claim 1, and p is 1,2,3,4,5,6,7,8 or 9.

6. according to the metal complex of one of claim 1 to 5 item, wherein K represents the metal complex of general formula I I.

7. according to the metal complex of claim 6, R wherein ²And R ³Be hydrogen or C independently of each other ₁-C ₄-alkyl.

8. according to the metal complex of one of claim 1 to 7, wherein at described formula-C _nF _2nE is a fluorine atom among the E.

9. according to the metal complex of one of claim 1 to 8 item, wherein L represents Methionin group (Vc) in general formula I.

10. according to the metal complex of one of claim 1 to 8, wherein L represents diamine groups (Va) or (Vb) in general formula I.

11. according to the metal complex of one of claim 1 to 10 item, wherein U represents-CH in metal complex K ₂-or-C ₆H ₄-O-CH ₂-ω, wherein ω represents and-connection site that CO-is connected.

12. the metal complex of claim 2 is used to prepare the contrast Material Injection Protocols that supplies NMR and x X-ray diagnosis X to use.

13. the application of the metal complex of claim 12 is used to prepare for the contrast medium that blocks and downright bad video picture is used.

14. the metal complex of claim 3 is used to prepare the contrast Material Injection Protocols that supplies radiodiagnosis and radiotherapy to use.

15. the metal complex of claim 2 is used for preparing the contrast Material Injection Protocols of using for the lymphography of diagnosing lymphsystem to change.

16. the metal complex of claim 2 is used to prepare the contrast Material Injection Protocols of using for the diagnosis diseases associated with inflammation.

17. the metal complex of claim 2 is used to prepare the contrast Material Injection Protocols for showing that arteriosclerosis plaque is used.

18. the metal complex of claim 2 is used to prepare the contrast Material Injection Protocols of using for diagnosis of cardiovascular diseases.

19. the metal complex of claim 2 is used to prepare the contrast Material Injection Protocols of using for tumor imaging.

20. the metal complex of claim 2 is used to prepare the contrast Material Injection Protocols that the video picture of blood supply pond is used.

21. a medicine, it contains normally used additive in compatible compound of the physiology of at least a claim 1 to 11 and the optional galenical.

22. a method for preparing the perfluoroalkyl-containing complexes of the nitrogenous connection based structures of having of general formula I,

Wherein K has the implication of the metal complex of the general formula I I to IV in the claim 1, and L, Q, X, R and R _fHave the implication in the claim 1,

Wherein:

Make the carboxylic acid of general formula I Ia

R wherein ⁵For ordination number is 21-29,31-33,37-39,42-44,49 or 57-83

Metal ion Equivalent or carboxyl-protecting group, and R ², R ³Have above-mentioned implication with U, or the carboxylic acid of general formula III a