JP2009501174A - Perfluoroalkyl-containing complex, production method and use thereof - Google Patents

Abstract

  The present invention relates to a substance of interest characterized by the claims, namely a perfluoroalkyl-containing metal complex comprising a group of general formula I containing nitrogen, a process for production and the NMR field and x-ray diagnostics, radiodiagnosis and radiotherapy Furthermore, it relates to lymphatic imaging in the MRT field and its use in blood pool images.

Description

  The present invention relates to a test substance characterized in the claims, namely a perfluoroalkyl-containing metal complex comprising a nitrogen-containing group of general formula I, a process for its preparation and NMR and x-ray diagnostics, radiodiagnosis and radiotherapy, MRT lymphography and its use in blood pool images. Nuclear spin resonance tomography for visualization of different physiological and pathophysiological structures and thus improved diagnostic information, ie location and severity of disease, selection and monitoring of effective target treatment and prevention ( MRT) using perfluoroalkyl-containing metal complexes.

  The compounds in the present invention are suitable for tumor diagnosis and lymphatic imaging in a rather specific way in infarct and necrosis.

  It is known in the field of nuclear magnetic resonance that several fluorine-containing compounds can be used in the image area. In most cases, however, such compounds have been proposed only for use in fluorine-19 images and are suitable only for this application. Such compounds are described, for example, in U.S. Pat. No. 4,639,364 (Mallinckrodt), DE4203254 (Max-Planck-Gesellschaft), WO93 / 07907 (Mallinckrodt), US4586511 (Children's Hospital Medical 63A, U.S. Pat. (University of Cincinnati, Children's Hospital Research Foundation) and WO 94/22368 (Molecular Biosystems).

  Additional fluorine-containing compounds that can be used in the image are US 5362478 (VIVORX), US Pat. No. 4,586,511, DE 400008179 (Schering), WO 94/05335 and WO 94/22368 (both molecular biosystems), EP 292306 (TERUMO Kabushiki EP 62, TERUMO Kabushiki EP 62). TERUMO Kabushiki Kaisha) and DE 4317588 (Schering).

In a compound containing fluorine and iodine elements, interaction between two nuclei does not occur, but in a compound containing fluorine and paramagnetic center (group, metal ion), strong interaction occurs, and the strong The interaction is expressed by shortening the relaxation time of the fluorine nucleus. The degree of this effect is determined by the number of unpaired electrons in the metal ion (Gd ³⁺ > Mn ²⁺ > Fe ³⁺ > Cu ²⁺ ) and the dissociation between the paramagnetic ion and the ¹⁹ F atom.

  The more unpaired electrons of the metal ion exist and the more the metal ion is carried by fluorine closer, the greater the reduction in the fluorine nucleus relaxation time.

  It is clear that the relaxation time, which is a function of the interval from the paramagnetic ion, is shortened in all nuclei with non-uniform spin numbers, and therefore gadolinium compounds are widely used as contrast agents for nuclear spin tomography in the case of protons. (Magnevist®, Proance®, Omniscan® and Dotarem®).

However, in the ¹ H-MR image ( ¹ H-MRI), the proton relaxation time T ¹ or T ² , that is, the relaxation time of the fluorine nucleus, is measured and used first for the proton of water. The quantitative measurement of the reduction in relaxation time is the relaxation ability [L / mmol. s]. In order to shorten the relaxation time, a paramagnetic ion complex is used effectively. In the table below, the mitigating ability of some commercial formulations is shown.

  In these compounds, only the interaction between protons and gadolinium ions occurs. Therefore, the relaxation capacity of these contrast agents in water is about 4 [L / mmol. s].

  Therefore, both the fluorine compound for fluorine-19 image used for shortening the relaxation time of fluorine nucleus and the non-fluorine-containing compound for measuring the relaxation time of water proton are effectively used for MR images.

  The introduction of perfluorocarbon-containing groups into the combination of known properties suitable only for paramagnetic contrast agents, i.e. fluorine imaging compounds and the compounds used for proton imaging, is very surprisingly the relaxation capacity associated with the protons of water. Also increase rapidly. 3.5-3.8 [L / mmol., Already mentioned for some commercial products in the above table. s] and no longer 10-50 [L / mmol. s] is reached.

  Perfluoroalkyl-containing metal complexes are already known from DE 1960333.1, WO 99/01161, DE 19914101, DE 10040381 and DE 10040858. However, in most cases the compatibility is insufficient so that these compounds cannot be used satisfactorily for all applications. Therefore, there is still a need for MRT contrast agents that have excellent image properties and at the same time are highly suitable for performing non-invasive diagnostic methods. This is important, for example, when diagnosing tumors involving hygiene metastases and distributing contrast agents throughout the body.

  A malignant tumor can metastasize within a cluster of regional lymph nodes, thereby also including several lymph node regions. Thus, lymph node metastasis is found in approximately 50-69% of all patients with malignant tumors (Elke, Lymphographie [Lymphography], in: Frommmold, Stender, Thurn (Eds.), Radiodioliskin Dikinstikink Rickinkindinkindinokindinkinkindinkinkindinkinkindinkinkindkinkin Diagnosis in Clinical Studies and in Practice], Volume IV, Thime Verlag Stuttgart, 7th Ed., 434-496, 1984). Diagnosis of the onset of lymph node metastasis is one of the most important for the treatment and prognosis of malignant diseases. Using modern imaging methods (CT, US and MRI), lymphatic drainage of malignant tumors is not very well detected because in most cases only the size of the lymph nodes can be used as a diagnostic criterion. Therefore, small metastasis of non-hypertrophic lymph nodes (<2 cm) cannot be distinguished from lymph node hyperplasia that has not developed malignancy (Steinkamp et al., Sonographie undenmann nerdomntikntik von m Hals [Sonography and Nuclear Spin Tomography: Differential Diagnosis of Reactive Lymph Node Enlargement and Lymph Node MetaNess ol.Diagnostic. 33: 158, 1992).

  When using certain contrast agents, it is desirable to be able to distinguish between lymph nodes with metastatic onset and hyperplastic lymph nodes.

  Direct x-ray lymphography (injecting an oily contrast medium suspension into the corresponding lymphatic vessels) is known as an invasive method, which can visualize only a few lymph drainage areas and is rarely used .

  Alternatively, fluorescently labeled dextran can be used experimentally in animal studies to observe lymphatic drainage after stroma administration. After interstitial / intradermal administration, all common markers used for visualization of lymphatic tracts and lymph nodes are generally substances that have a particulate nature (“particulate” such as emulsions and nanocrystalline suspensions). Liquid) or a large polymer (see WO90 / 14846 above). The previously described formulations have been shown to be still unsuitable for indirect lymphography, because of poor diagnostic efficiency due to poor local and systemic compatibility and small lymph node pathways Because.

  Since the visualization of lymph nodes is one of the most important for early detection of metastatic development in cancer patients, lymph node-specific contrast products are greatly needed in the diagnosis of the changes in the lymphatic system, and these This contrast formulation is characterized by very good compatibility. In the terminology of the present invention, the lymphatic system includes both lymph nodes and lymph vessels. Therefore, the substance of the present invention is suitable for diagnosis of changes in the lymphatic system, preferably diagnosis of changes in lymph nodes and / or lymph vessels, specifically diagnosis of lymph node metastasis.

  The concentration of contrast agent with the highest potential and stability is just as desirable as the most likely lymph concentration relevant to diagnosis across several lymphatic regions. By rapidly and completely excreting the contrast agent, the burden on the whole body should be kept low. In radiotherapy, it is important to start as early as possible, as early as within a few hours after contrast agent administration. Good compatibility is required.

  In short, it is desirable to have a lymph node-specific contrast agent that can be used to visualize both primary tumors and occult lymph node metastases during the course of diagnosis.

  Another important medical area is necrosis or infarct detection, localization and monitoring. Thus, myocardial infarction is not a static process, but rather a dynamic process over a long period (weeks to months). The disease goes through about a three-phase process, which is not strictly separated from each other, but rather overlaps. The progression of myocardial infarction, which is the first phase, includes 24 hours after the infarction, and during this period, the progression of destruction includes a shock wave (wavefront phenomenon) from the subendocardium to the myocardium. Phase II, existing infarctions involve immobilization of areas of fibrosis (fibrosis) that occur as a healing process. A third phase, old infarction, begins after all the destroyed tissue has been replaced with fibrotic scar tissue. During this period, a large rebuild occurs.

  To date, no accurate and reliable method is known that can diagnose the current phase of myocardial infarction in a living patient. In order to assess myocardial infarction, knowing how large a tissue portion that has disappeared in an infarct is and at what point the disappearance occurs is one of the crucial reasons, This is because the type of treatment is determined by this recognition.

  Infarctions occur not only in the myocardium, but also in other tissues, particularly the brain.

  Infarctions can be healed to some extent, but in the case of necrosis, which is a localized tissue death, only the sequelae that are detrimental to the rest of the body can be prevented or at least alleviated. Necrosis can progress through a variety of modes, damage, chemicals, lack of oxygen or radiation. In the case of infarctions, recognition of the extent and type of necrosis is important in further drug therapy.

  Therefore, trials have already been conducted early on to improve the location of infarctions and necrosis using contrast agents in non-invasive processes such as scintigraphy or nuclear spin tomography. In the reference literature, tests using porphyrins for the necrosis dominate. However, the results obtained show an inconsistent state. In addition, porphyrins tend to deposit on the skin, which leads to photosensitization.

  Concerning necrosis and infarct images, contrast agents that are not derived from the porphyrin skeleton are described in DE 19744403 (Schering AG), DE 1974404 (Schering AG) and WO 99/17809 (EPIX). However, to date there are no compounds yet that can be used satisfactorily as contrast agents for infarct and necrosis and at the same time are characterized by excellent compatibility.

  Similar problems exist in the area of compounds that can be used to diagnose thrombin or atherosclerotic plaques. No compound can be used satisfactorily as a contrast agent for visualizing thrombin or atherosclerotic plaques while at the same time being characterized by excellent compatibility.

  The object of the present invention therefore has, on the one hand, excellent imaging properties as MRT contrast agents, in particular tumor and necrosis and / or lymphatic imaging and / or blood pool images and / or thrombin or arteries. It was suitable to visualize curable plaques and at the same time to make available contrast agents distinguished by excellent compatibility.

The object of the present invention is the general formula I

（式中、
Ｒ¹は、水素原子または原子数２１〜２９、３１〜３３、３７〜３９、４２〜４４、４９または５７〜８３の金属イオン当量を意味し、
ただし、少なくとも２個のＲ¹が金属イオン当量を表し、
Ｒ²およびＲ³は、それぞれ独立して、水素、Ｃ₁−Ｃ₇−アルキル、ベンジル、フェニル、−ＣＨ₂ＯＨまたは−ＣＨ₂ＯＣＨ₃を表し、
Ｕは、−Ｃ₆Ｈ₄−Ｏ−ＣＨ₂−ω、−（ＣＨ₂）_1-5−ω、フェニレン基、−ＣＨ₂−ＮＨＣＯ−ＣＨ₂−ＣＨ（ＣＨ₂ＣＯＯＨ）−Ｃ₆Ｈ₄−ω−、−Ｃ₆Ｈ₄−（ＯＣＨ₂ＣＨ₂）_0-1−Ｎ（ＣＨ₂ＣＯＯＨ）−ＣＨ₂−ωまたはＣ₁−Ｃ₁₂−アルキレンあるいは−（ＣＨ₂）_7-12−Ｃ₆Ｈ₄−Ｏ基を表し、これは場合により１個または複数個の酸素原子、−ＮＨＣＯ基１〜３個または−ＣＯＮＨ−基１〜３個により中断および／または−（ＣＨ₂）_0-5ＣＯＯＨ基１〜３個により置換され、ωは、−ＣＯ−への結合部位を表す。）
または一般式ＩＩＩ

（式中、Ｒ¹は、上記の意味を有し、Ｒ⁴は、水素またはＲ¹下に挙げられる金属イオン当量を表し、Ｕ¹は、−Ｃ₆Ｈ₄−Ｏ−ＣＨ₂−ωもしくは−（ＣＨ₂）_p’−基を表し、ωは、−ＣＯ−への結合部位を意味し、ｐ’は、１〜４の整数である。）
または一般式ＩＶ

（式中、Ｒ¹およびＲ²は、上記の意味を有する。）
または一般式ＶＡもしくはＶＢ

（式中、Ｒ¹は、上記の意味を有する。）
または一般式ＶＩ

（式中、Ｒ¹は、上記の意味を有する。）
または一般式ＶＩＩ

（式中、Ｒ¹およびＵ¹は、上記の意味を有し、ωは、−ＣＯ−への結合部位を意味する。）
または一般式ＶＩＩＩ

（式中、Ｒ¹は、上記の意味を有し、
Ｕ²は、直鎖もしくは分岐鎖、飽和もしくは不飽和Ｃ₁−Ｃ₂₀アルキレン基を表し、これは場合によりイミノ、フェニレン、フェニレンオキシ、フェニレンイミノ、アミド、ヒドラジド、カルボニル、エステル基、（１個または複数個の）酸素、硫黄および／または窒素原子（１個または複数個の）を含有し、場合によりヒドロキシ、メルカプト、オキソ、チオキソ、カルボキシ、カルボキシアルキル、（１個または複数個の）エステルおよび／またはアミノ基により置換され、
場合により基Ｋに存在する遊離酸基は、場合により有機および／または無機塩基またはアミノ酸あるいはアミノ酸アミドの塩として存在することができ、
Ｌは、以下の基ＩＸａ）〜ＩＸｃ）から選択される基を表し、

（式中、ｎ’およびｍ’は、それぞれ独立して、０〜４の整数を表し、ｍ’＋ｎ’≧１；好ましくは、ｍ’＋ｎ’は１、２または３に等しく、
Ｒ⁸およびＲ^8’は、それぞれ独立して、−Ｈまたは−ＯＨのどちらかであり、ｍ’＋ｎ’＞１、−（ＣＲ⁸Ｒ^8’）各基は異なっていてよく、
Ｗは、直接結合、−Ｏ−またはフェニレン基のどれかであり、これは、場合によりヒドロキシ基１〜４個により置換されることができ、
ｑ’は、１、２、３または４のいずれかであり、
αは、Ｌが錯体Ｋへの結合部位であり、βは、Ｌの基Ｑへの結合部位であり、γは、Ｌが基Ｘへの結合部位である。））
の金属錯体を表し、
Ｘは、式（ＶＩ）

（式中、Ｙは、直接結合、−ＣＯ−またはＮＲ⁶基を意味し、Ｒ⁶は、−Ｈまたは直鎖もしくは分岐鎖、飽和もしくは不飽和のＣ₁−Ｃ₁₅炭素鎖を表し、これは、Ｏ原子１〜４個、−ＮＨＣＯ基１〜３個、ＣＯＮＨ基１〜３個、ＳＯ₂基１〜２個、硫黄原子１〜２個、ＮＨ基１〜３個またはフェニレン基１〜２個により中断されることができ、
これは、場合によりＯＨ基１〜２個、ＮＨ₂基１〜２個、−ＣＯＯＨ基１〜２個または−ＳＯ₃Ｈ基１〜２個により置換されることができ、
これは、場合によりＯＨ基１〜１０個、−ＣＯＯＨ基１〜５個、−ＳＯ₃Ｈ基１〜２個、ＮＨ₂基１〜５個、またはＣ₁−Ｃ₄−アルコキシ基１〜５個により置換され、Ｇは、−Ｏ−または−ＳＯ₂−のどちらかを意味し、
ｓおよびｓ’はそれぞれ独立して、１または２のどちらかを意味し、ｔは０または１のどちらかを意味し、
ρは、ＸのＬへの結合部位を表し、ζは、ＸのＲ_fへの結合部位を表す。）
の基を表す。）］
の窒素含有リンカー構造を有するペルフルオロアルキル含有錯体により得られる。 [Wherein R represents either a monosaccharide or an oligosaccharide group bonded via 1-OH;
In this case, Q is
δ-CO- (CH ₂ ) _{n ″} -ε
δ-NH- (CH ₂ ) _{n ″} -ε
δ− (CH ₂ ) _m −ε
(Where
n ″ is an integer from 1 and 5;
m is an integer from 1 and 6;
δ represents a binding site to the linker L, and ε represents a binding site to the group R. )
Means a group selected from
Or R means one of the following, where Q means a direct bond and R is
In the formula, R ¹ means a hydrogen atom or a metal ion equivalent of 20 to 29, 31 to 33, 37 to 39, 42 to 44, 49 or 57 to 83 atoms,
The groups R ² , R ³ , R ⁴ , U and U ¹ are a complex K of the general formulas II to V having the meaning indicated below,
Or —CO—, —NR ⁷ — or a carbon chain having 1 to 30 C atoms bonded to the linker L via a direct bond,
(This may be linear or branched, saturated or unsaturated, and optionally 1 to 10 oxygen atoms, 1 to 5 —NHCO groups, 1 to 5 —CONH groups, 1 to 2 sulfur atoms. Interrupted by 1 to 5 —NH groups or 1 to 2 phenylene groups, optionally 1 to 2 OH groups, 1 to 2 NH ₂ groups, 1 to 2 —COOH groups or 1 —SO ₃ H group Can be replaced by ~ 2,
Optionally substituted by 1 to 10 OH groups, 1 to 5 —COOH groups, 1 to 2 SO ₃ H groups, 1 to 5 NH ₂ groups or _{1 to} 5 C ₁ -C ₄ -alkoxy groups. , R ⁷ represents H or C ₁ -C ₄ -alkyl. )
Means a polar group selected from
R _f is a perfluoro linear or branched carbon chain having the formula —C _n F _2n E, where E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n is 4-30. Represents an integer of
K represents the general formula II

(Where
R ¹ means a hydrogen atom or a metal ion equivalent of 21 to 29, 31 to 33, 37 to 39, 42 to 44, 49 or 57 to 83 atoms,
Provided that at least two R ¹ represent metal ion equivalents;
R ² and R ³ each independently represent hydrogen, C ₁ -C ₇ -alkyl, benzyl, phenyl, —CH ₂ OH or —CH ₂ OCH ₃ ;
U represents —C ₆ H ₄ —O—CH ₂ —ω, — (CH ₂ ) _1-5 —ω, a phenylene group, —CH ₂ —NHCO—CH ₂ —CH (CH ₂ COOH) —C ₆ H _{4. -ω -, - C 6 H 4} - (OCH 2 CH 2) 0-1 -N (CH 2 COOH) -CH 2 -ω or C ₁ -C ₁₂ - alkylene or - (CH _{2) 7-12} -C Represents a ₆ H ₄ —O group, optionally interrupted by one or more oxygen atoms, 1 to 3 —NHCO groups or 1 to 3 —CONH— groups and / or — (CH ₂ ) _{0 — 5} is substituted by 1-3 COOH groups, omega represents the binding site to -CO-. )
Or general formula III

(Wherein R ¹ has the above-mentioned meaning, R ⁴ represents hydrogen or a metal ion equivalent listed under R ¹ , and U ¹ represents —C ₆ H ₄ —O—CH ₂ —ω or - (CH _{2) p '-} represents a radical, omega denotes a binding site for -CO-, p' is an integer of 1 to 4).
Or general formula IV

(In the formula, R ¹ and R ² have the above-mentioned meanings.)
Or general formula VA or VB

(Wherein R ¹ has the above-mentioned meaning.)
Or general formula VI

(Wherein R ¹ has the above-mentioned meaning.)
Or general formula VII

(In the formula, R ¹ and U ¹ have the above-mentioned meanings, and ω means a binding site to —CO—.)
Or general formula VIII

Wherein R ¹ has the above meaning,
U ² represents a straight chain or branched chain, saturated or unsaturated C ₁ -C ₂₀ alkylene group, which may optionally be an imino, phenylene, phenyleneoxy, phenyleneimino, amide, hydrazide, carbonyl, ester group, (one Or oxygen), sulfur and / or nitrogen atom (s), optionally hydroxy, mercapto, oxo, thioxo, carboxy, carboxyalkyl, ester (s) and Substituted with an amino group,
The free acid group optionally present in the group K can optionally be present as an organic and / or inorganic base or a salt of an amino acid or amino acid amide,
L represents a group selected from the following groups IXa) to IXc):

(Wherein n ′ and m ′ each independently represents an integer of 0 to 4, m ′ + n ′ ≧ 1; preferably m ′ + n ′ is equal to 1, 2 or 3;
R ⁸ and R ^{8 ′} are each independently either —H or —OH, and m ′ + n ′> 1, — (CR ⁸ R ^{8 ′} ) groups may be different,
W is either a direct bond, -O- or a phenylene group, which can optionally be substituted by 1 to 4 hydroxy groups;
q ′ is one of 1, 2, 3 or 4;
α is the binding site of L to the complex K, β is the binding site of L to the group Q, and γ is the binding site of L to the group X. ))
Represents a metal complex of
X is the formula (VI)

Wherein Y represents a direct bond, —CO— or an NR ⁶ group, R ⁶ represents —H or a linear or branched, saturated or unsaturated C ₁ -C ₁₅ carbon chain, Are 1 to 4 O atoms, 1 to 3 —NHCO groups, 1 to 3 CONH groups, 1 to ₂ SO ₂ groups, 1 to 2 sulfur atoms, 1 to 3 NH groups, or 1 to 2 phenylene groups. Can be interrupted by two,
This can optionally be substituted by 1-2 OH groups, 1-2 NH ₂ groups, 1-2 COOH groups or 1-2 SO ₃ H groups,
This may optionally be 1 to 10 OH groups, 1 to 5 —COOH groups, 1 to 2 —SO ₃ H groups, 1 to 5 NH ₂ groups, or _{1 to} 5 C ₁ -C ₄ -alkoxy groups. And G represents either —O— or —SO ₂ —;
s and s ′ each independently represent either 1 or 2, t represents either 0 or 1,
ρ represents the binding site of X to L, and ζ represents the binding site of X to R _f . )
Represents a group of ]]
Of a perfluoroalkyl-containing complex having a nitrogen-containing linker structure.

In a preferred embodiment, R ⁶ is H or a C ₁ -C ₆ -alkyl group, which can be interrupted by 1 to 3 O atoms and can be substituted by 1 to 4 OH groups.

In a particularly preferred embodiment, R ⁶ is a C ₁ -C ₄ alkyl group.
In a preferred embodiment G represents a —O— group.
In a particularly preferred embodiment, t = 0.

  In preferred embodiments, W is a direct bond.

In a preferred embodiment, the group R attached to the linker L via —CO—, —NR ⁷ — or a direct bond is interrupted by 1 to 10 oxygen atoms and / or substituted by 1 to 10 OH groups. It is a carbon chain having 1 to 30 atoms.

In particularly preferred embodiments, R is —CO—, —NR ⁷ — or a C ₁ -C ₁₂ carbon chain attached to L via a direct bond, which is interrupted by 1 to 6 oxygen atoms and / or Substituted by 1 to 6 OH groups.

  If the compounds in the present invention are intended for use in NMR diagnostics, the signal group metal ion must be paramagnetic. Specifically, divalent and trivalent ions of elements having 21 to 29, 42, 44, and 58 to 70 atoms. For example, suitable ions include chromium (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III) and ytterbium (III ) Ion. Because of their high magnetic efficiency, gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), iron (III) and manganese (II) ions are particularly preferred.

  For the use of the compounds in the present invention in nuclear medicine (radiodiagnosis and radiotherapy), the metal ions must be radioactive. For example, radioisotopes of elements having 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 and 77 are suitable. Technetium, gallium, indium, rhenium and yttrium are preferred.

  When the compound in the present invention is intended to be used for x-ray diagnosis, the metal ion is preferably derived from an element having a large number of atoms so that sufficient x-ray absorption can be obtained. In this regard, diagnostic agents containing physiologically compatible complex salts with metal ions of the elements 25, 26 and 39 and 57-83 have been found to be suitable.

  Manganese (II), iron (II), iron (III), praseodymium (III), neodymium (III), samarium (III), gadolinium (III), ytterbium (III) or bismuth (III) ions, specifically Dysprosium (III) ions and yttrium (III) ions are preferred.

Optionally, the acidic hydrogen atoms present in R ¹ , ie those atoms not substituted by a central ion, are optionally fully or partially substituted by inorganic and / or organic bases or amino acid or amino acid amide cations. Can.

  For example, suitable inorganic cations are lithium ions, potassium ions, calcium ions and specifically sodium ions. Suitable organic base cations are ie primary, secondary or tertiary amines such as ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and in particular N-methylglucamine. It is from Kamin. For example, suitable amino acid cations are those of lysine, arginine and ornithine and amides of other acidic or neutral amino acids.

  Particularly preferred compounds of the general formula I are those having the macrocyclic compound K of the general formula II.

The group U of the metal complex K preferably means —CH ₂ or C ₆ H ₄ —O—CH ₂ —ω, where ω represents the binding site to —CO—.

In preferred embodiments, U ² is a C ₁ -C ₆ alkylene chain, which is optionally interrupted by 1 to 2 —NHCO groups and / or 1 to 2 O atoms, and —OH groups 1 to 3 Can be replaced by

The group U ² of the metal complex K is preferably specifically,
Linear alkylene group having 1 to 6 C atoms, specifically 2, 3 or 4 C atoms, or linear alkylene group having 1 to 6 C atoms, specifically C atoms 2, 3 Or 4, which is interrupted by one O atom, or a linear alkylene group having 1 to 6 C atoms, specifically 2, 3 or 4 C atoms, which contains a —NHCO group Means that.

In a particularly preferred embodiment, U ² is an ethylene group.

The alkyl groups R ² and R ³ of the macrocycle of general formula II may be linear or branched. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl and 1,2-dimethylpropyl. it can. R ² and R ³ are each independently preferably hydrogen or C ₁ -C ₄ -alkyl.

In a highly preferred embodiment, R ² represents methyl and R ³ represents hydrogen.

The benzyl group or phenyl group R ² or R ³ of the macrocyclic compound K of general formula II can also be substituted in the ring.

  In another preferred embodiment of the invention, R is a monosaccharide group having 5 to 6 C atoms, preferably glucose, mannose, galactose, ribose, arabinose or xylose or a desoxy sugar thereof, such as 6-desoxygalactose ( Fucose) or 6-desoxymannose (rhamnose) or peralkylated derivatives thereof. Particularly preferred are glucose, mannose and galactose, specifically mannose.

の１つおよび直接結合を意味するＱを有する式（ＩＩ）の錯体から選択される。
（式中、Ｒ¹、Ｒ²、Ｒ³およびＵは、式（ＩＩ）の上記の通りに定義され、
ｐは１、２、３、４、５、６、７、８または９のいずれかであり、
Ｒ¹は、ＨまたはＣＨ₃のどちらかであり、Ｒ’’は、ＨまたはＣ₁−Ｃ₄アルキル基のいずれかであり、
ｐは、好ましくは１、２、３または４である。）
本明細書に示される極性基は市販製品であり、または参照文献に記載される方法に従い製造される。
Ｃａｓｓｅｌ ｅｔ ａｌ．，Ｅｕｒ．Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２００１，５，８７５−８９６
Ｗｈｉｔｅｓｓｉｄｅｓ ｅｔ ａｌ．，ＪＡＣＳ，１９９４，５０５７−５０６２
Ｖｏｅｇｔｌｅ ｅｔ ａｌ．，Ｌｉｅｂｉｇｓ Ａｎｎ．Ｃｈｅｍ．，１９８０，８５８−８６２
Ｌｉｕ ｅｔ ａｌ．，Ｃｈｅｍ．Ｃｏｍｍｕｎ．，２００２，５９４
Ｍｉｔｃｈｅｌｌ ｅｔ ａｌ．，Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍ．，１９８４，６９７−６９９
Ｂａｒｔｓｃｈ ｅｔ ａｌ．，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９８４，４０７６−４０７８
Ｋｅａｎａ ｅｔ ａｌ．，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９８３，２６４７−２６５４
非常に好ましい実施形態において、Ｒは式：
−Ｃ（Ｏ）ＣＨ₂Ｏ［（ＣＨ₂）₂Ｏ］_pＲ’
の基であり、これを−ＣＯ−を介してＬに結合する。 In another preferred embodiment of the invention, R is a group

And a complex of formula (II) having Q meaning a direct bond.
Wherein R ¹ , R ² , R ³ and U are defined as above for formula (II),
p is one of 1, 2, 3, 4, 5, 6, 7, 8 or 9;
R ¹ is either H or CH ₃ , R ″ is either H or a C ₁ -C ₄ alkyl group,
p is preferably 1, 2, 3 or 4. )
The polar groups shown herein are commercial products or are made according to the methods described in the references.
Cassel et al. , Eur. J. et al. Org. Chem. , 2001, 5, 875-896
Whitesides et al. , JACS, 1994, 5057-5062
Voegtle et al. , Liebigs Ann. Chem. , 1980, 858-862
Liu et al. , Chem. Commun. , 2002, 594
Mitchell et al. , Heterocyclic Chem. , 1984, 697-699
Bartsch et al. , J .; Org. Chem. , 1984, 4076-4078.
Keana et al. , J .; Org. Chem. , 1983, 2647-2654.
In a highly preferred embodiment, R is of the formula:
_{-C (O) CH 2 O [} (CH 2) 2 O] p R '
Which is bonded to L via -CO-.

p and R ′ have the meanings indicated above, and R ′ is particularly preferably a CH ₃ group.

In another preferred embodiment, Q is
δ-CO- (CH ₂ ) _{n ″} -ε
(Where
n ″ is an integer from 1 and 5;
At the same time L has the meaning of the group of formula IXa or IXb. )
Means a group selected from
In another preferred embodiment, Q is
δ-NH- (CH 2) _{n ″} -ε
(Where
n ″ is an integer from 1 and 5;
At the same time, L means a group of IXc. )
Means a group selected from

Among the compounds of the general formula I in the present invention, it is further preferred that R _f is —C _n F _{2n + 1} ; that is, E in the formula —C _n F _2n E means a fluorine atom. n preferably represents an integer of 4 to 15. Quite preferably the group _{-C 4 F 9, -C 6 F} 13, -C 8 F 17, a group of -C ₁₂ F ₂₅ and -C ₁₄ F ₂₉ and compounds recited in the present embodiment.

In a preferred embodiment of the invention, the nitrogen-containing group L of the general formula I representing “skeleton” means an amino acid group (Vc).
In another preferred embodiment, the nitrogen-containing group L of general formula I represents a diamine group of formula (IXb) or (IXa).

（Ｋは、一般式ＩＩ〜ＩＶの金属錯体を意味し、Ｌ、Ｑ、Ｘ、ＲおよびＲ_fは、上記に示された意味を有する。）
の窒素含有リンカー構造を有するペルフオロアルキル含有金属錯体は、当技術分野に公知の方法で、一般式ＩＩａ

（式中、Ｒ⁵は、原子数２１〜２９、３１〜３３、３７〜３９、４２〜４４、４９または５７〜８３の金属イオン当量あるいはカルボキシル保護基を意味し、Ｒ²、Ｒ³およびＵは、上記の意味を有する。）
のカルボン酸
または一般式ＩＩＩａ

（式中、Ｒ⁴、Ｒ⁵およびＵ¹は、上記の意味を有する。）
のカルボン酸
または一般式ＩＶａ

（式中、Ｒ⁵およびＲ²は、上記の意味を有する。）
のカルボン酸
または一般式ＶａもしくはＶｂ

（式中、Ｒ⁵は、上記の意味を有する。）
のカルボン酸
または一般式ＶＩａ

（式中、Ｒ⁵は、上記の意味を有する。）
のカルボン酸
または一般式ＶＩＩａ

（式中、Ｒ⁵およびＵ¹は、上記の意味を有する。）
のカルボン酸、
または一般式ＶＩＩＩａ

（式中、Ｒ⁵およびＵ²は、上記の意味を有する。）
のカルボン酸
が、場合により活性した形態において、一般式ＸＩ

（式中、Ｌ、Ｒ、Ｒ_f、ＱおよびＸは、カップリング反応において、上記に示された意味を有し、場合により存在する保護基を場合により逐次的に切断して一般式Ｉの金属錯体を形成し、
または
Ｒ⁵が保護基を意味する場合、当技術分野において公知である方法の逐次的ステップのこれらの保護基を切断後に、原子数２１〜２９、３１〜３３、３７〜３９、４２〜４４、４９または５７〜８３の元素の少なくとも１種の金属酸化物または金属塩と反応し、次いで所望の場合、場合により存在する酸性水素原子が無機および／または有機塩基、アミノ酸またはアミノ酸アミドの陽イオンにより置換される。）のアミンと反応することにより製造される。 Formula I

(K means a metal complex of the general formulas II to IV, and L, Q, X, R and R _f have the meanings indicated above.)
A perfluoroalkyl-containing metal complex having a nitrogen-containing linker structure of the general formula IIa is a method known in the art.

(In the formula, R ⁵ means a metal ion equivalent of 21 to 29, 31 to 33, 37 to 39, 42 to 44, 49 or 57 to 83, or a carboxyl protecting group, and R ² , R ³ and U Has the above meaning.)
Or a carboxylic acid of the general formula IIIa

(In the formula, R ⁴ , R ⁵ and U ¹ have the above-mentioned meanings.)
Or a carboxylic acid of the general formula IVa

(In the formula, R ⁵ and R ² have the above-mentioned meanings.)
A carboxylic acid of the general formula Va or Vb

(Wherein R ⁵ has the above meaning.)
Or a carboxylic acid of the general formula VIa

(Wherein R ⁵ has the above meaning.)
Or a carboxylic acid of the general formula VIIa

(Wherein R ⁵ and U ¹ have the above meanings.)
Carboxylic acid,
Or general formula VIIIa

(Wherein R ⁵ and U ² have the above meanings.)
In an optionally activated form of the general formula XI

(Wherein L, R, R _f , Q and X have the meanings indicated above in the coupling reaction, optionally capping the optionally present protecting groups optionally in the general formula I). Forming a metal complex,
Or when R ⁵ means a protecting group, after cleavage of these protecting groups in sequential steps of methods known in the art, the number of atoms 21-29, 31-33, 37-39, 42-44, Reacts with at least one metal oxide or metal salt of the element 49 or 57-83 and then, if desired, the optionally present acidic hydrogen atom is capped by an inorganic and / or organic base, amino acid or amino acid amide cation. Is replaced. ) To react with amines.

  The process for producing this metal complex carboxylic acid amide is known from DE 19652386.

  A mixture used in the coupling reaction and consisting of the metal complex carboxylic acid IIIb, which is less than 5, preferably less than 0, preferably in the protected form relative to the carboxy and / or hydroxy groups and metal complex carboxylic acid present. Contains 5 to 2 molecular equivalents of at least one solubilizing substance but is produced and isolated in an upstream reaction step (eg, by concentrating the aqueous or water-miscible solution of the component by evaporation, lyophilization or spray drying) Or by precipitation with an organic solvent from such a solution), and then can be reacted with a dehydrating agent and optionally a binding adjuvant in DMSO, optionally solubilizing material in situ in DMSO. Metal complex carboxylic acid, dehydrating agent and optionally binding adjuvant by adding to suspension It can be et formed.

  The reaction solution produced according to one of these methods is allowed to stand for pretreatment (acid activation) at 1-24, preferably 3-12 hours, 0-50 ° C., preferably at room temperature.

（式中、基Ｌ、Ｒ、Ｒ_f、ＱおよびＸは、上記に示された意味を有する。）のアミンを、溶媒を含まず、あるいは例えば、ジメチルスルホキシド、アルコール、例えば、メタノール、エタノール、イソプロパノールもしくはその混合物、ホルムアミド、ジメチルホルムアミド、水もしくは前記溶媒の混合物中、好ましくはジメチルスルホキシド中、水または水と混合される溶媒中に溶解した形態において添加する。アミド結合において、このように得られた反応溶液を０〜７０℃、好ましくは３０〜６０℃、１時間〜４８時間、好ましくは８〜２４時間静置する。 At this time, the general formula XI

(Wherein the groups L, R, R _f , Q and X have the meanings indicated above) without solvent, or for example dimethyl sulfoxide, alcohols such as methanol, ethanol, It is added in the form dissolved in isopropanol or a mixture thereof, formamide, dimethylformamide, water or a mixture of said solvents, preferably in dimethyl sulfoxide, in water or in a solvent mixed with water. In the amide bond, the reaction solution thus obtained is allowed to stand at 0 to 70 ° C., preferably 30 to 60 ° C., 1 hour to 48 hours, preferably 8 to 24 hours.

  In some cases, it has been found advantageous to use the reaction as an amine in its salt form, such as hydrobromic acid or hydrochloric acid. In order to release the amine, a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, tripropylamine, tributylamine, lithium hydroxide, lithium carbonate, sodium hydroxide or sodium carbonate is added.

  Then, optionally protecting groups still present are cleaved.

  Isolation of the reaction product is carried out according to methods known to those skilled in the art, preferably by precipitation with an organic solvent, preferably acetone, 2-butanone, diethyl ether, ethyl acetate, methyl-t-butyl ether, isopropanol or mixtures thereof. Is done. Additional purification can be performed, for example, by chromatography, crystallization, or ultrafiltration.

  As solubilizing substances, alkali salts, alkaline earth salts, trialkylammonium salts, tetraalkylammonium salts, urea, N-hydroxyimide, hydroxyaryltriazole, substituted phenols and heterocyclic amine salts are preferred. For example, the following can be mentioned: lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, lithium methanesulfonate, sodium methanesulfonate, lithium p-toluenesulfonate, p-toluene. -Sodium sulfonate, potassium bromide, potassium iodide, sodium chloride, magnesium bromide, magnesium chloride, magnesium iodide, tetraethylammonium p-toluenesulfonate, tetramethylammonium p-toluenesulfonate, pyridinium p-toluenesulfonate P-toluenesulfonic acid triethylammonium, 2-morpholinoethylsulfonic acid, 4-nitrophenol, 3,5-dinitrophenol, 2,4-dichlorophenol, N-hydroxysuccinimide, N-hy B carboxymethyl phthalimide, urea, tetramethylurea, an N- methylpyrrolidone, formamide and cyclic ureas, the above first five is preferred.

  As the dehydrating reagent, all drugs known to those skilled in the art are used. For example, carbodiimide and onium reagents such as dicyclohexylcarbodiimide (DCCI), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydroxychloride (EDC), benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexa Fluorophosphate (BOP) and O- (benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), preferably DCCI can be mentioned.

References describe, for example, the following appropriate methods:
Aktiverung von Carbonsaeuren. Uebersicht in Houben-Weyl, Methoden der Organischen Chemie [Activation of Carboxylic Acids. Survey in Houben-Weyl, Methods of Organic Chemistry], Volume XV / 2, Georg Thiem Verlag Stuttgart, 1974 (and J. Chem. Research (S) 1996, 1996).
Aktiverung mit Carbodiimiden [Activation with Carboimidides]. R. Schwyzer and H.C. Kappeler, Helv. 46: 1550 (1963).
E. Wuensch et al. , Vol. 100: 173 (1967).
Aktiverung mit carbodiimiden / Hydroxysuccinimid [Activation with Carbodiimides / Hydroxy Succinimide]: Am. Chem. Soc. 86: 1839 (1964) as well as J. et al. Org. Chem. 53: 3583 (1988). Synthesis 453 (1972).
Anhydride method, 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydrochinolin [Anhydride Method, 2-Ethoxy-1-phenyl-1, 2-diquinoquinine]: B. Belleau et al. , J .; Am. Chem. Soc. , 90: 1651 (1986), H .; Kunz et al. , Int. J. et al. Pept. prot. Res. , 26: 493 (1985) and J. Am. R. Voughn, Am. Soc. 73: 3547 (1951).
Imidazolid-Method [Imidazolide Method]: B. F. Gisin, R .; B. Menfield, D.M. C. Tosteon, Am. Soc. 91: 2691 (1969).
Saeurechlorid-Methodden, Thionylchlorid [Acid Chloride Methods, Thionyl Chloride]: Helv. 42: 1653 (1959).
Oxalyl chloride [Oxalyl Chloride]: Org. Chem. 29: 843 (1964).
As the optional binding adjuvants, all known to those skilled in the art are suitable (Houben-Weyl, Methoden der organischen Chemie, Volume XV / 2, Georg Thieme-Verlag, Stuttgart, 1974). Examples include 4-nitrophenol, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole, 3,5-dinitrophenol and pentafluorophenol. 4-Nitrophenol and N-hydroxysuccinimide are preferred, particularly preferred in this case being the first listed reagents.

  Cleavage of the protecting group is according to methods known to those skilled in the art, for example hydrolysis, hydrogenolysis, alkali saponification of the ester using alkali in aqueous alcohol at 0 ° C. to 50 ° C., mineral acid or for example tert- In the case of the butyl ester, trifluoroacetic acid is used [Protective Groups in Organic Synthesis, 2nd Edition, T. et al. W. Greene and P.M. G. M.M. Wuts, John Wiley and Sons, Inc. New York, 1991], in the case of benzyl esters carried out by acid saponification using hydrogen / palladium / carbon.

  The carboxylic acids of the general formulas IIa to VIIa used are either known compounds or are prepared, for example, according to the method described in this example. See DE10040381 and DE10040858. The preparation of carboxylic acids of the general formula IIa is therefore known from DE 19652386. The carboxylic acids of the general formula VIIIa used are prepared as described in WO 95/17451.

When R is a mono- or oligosaccharide, the perbenzylated sugar acid used as starting material can be obtained from Lockhoff, Angrew. Chem [Applied Chem. ] 1998, 110 No. 24, p. 3634ff. Can be manufactured in the same way. Thus, for example, the preparation of 1-O-acetic acid derived from perbenzylglucose can be achieved by reacting with hydroxyacetic acid ethyl ester via trichloroacetimidate, BF ₃ catalyst in THF, followed by saponification with NaOH in MeOH / THF. Performed over the stages.

As described in DE 10040381, in a more advantageous manner, the perbenzylated saccharide acid used as starting material can also be prepared with a perbenzylated 1-OH sugar dissolved in an organic solvent. The solvent is not water miscible and has the general formula XI:
Nu-L-COO-SG (XVIII)
(In the formula, Nu represents a leaving group, L represents — (CH ₂ ) _—n , (where n = 1 to 5), —CH ₂ —CHOH— or —CH (CHOH—CH _2). OH) —CHOH—CHOH—, where Sg represents a protecting group in the presence of a base and optionally a phase transfer catalyst. As a leaving group, for example, a group —Cl, —Br, —I, —OTs, —OMs, —OSO ₂ CF ₃ , —OSO ₂ C ₄ F ₉ or —OSO ₂ C ₈ F ₁₇ is substituted with an alkyl of the general formula XVIII Can be contained in the reagent.

  The protecting group is a general acid protecting group. These protecting groups are known to those skilled in the art (Protective Groups in Organic Syntheses, Second Edition, TW Greene and PMGM Wuts, John Wiley & Sons, Inc., New York 19).

  The reaction in the present invention can be carried out at 0 to 50 ° C., preferably from 0 ° C. to room temperature. The reaction time is 10 minutes to 24 hours, preferably 20 minutes to 12 hours.

  The base is added either in solid form, preferably in fine powder form or as a 10-70%, preferably 30-50% aqueous solution. As preferred bases NaOH and KOH are used.

As the non-water miscible organic solvent, for example, toluene, benzene, CF ₃ benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, MTB or a mixture thereof can be used in the alkylation method in the present invention.

Quaternary ammonium or phosphonium salts or crown ethers known in this regard are used as phase transfer catalysts in the process according to the invention, for example [15] -crown-5 or [18] -crown-6. Preferred are quaternary ammonium salts having four identical or different hydrocarbon groups on a cation selected from methyl, ethyl, propyl, isopropyl, butyl or isobutyl. The hydrocarbon group on the cation must be large enough to ensure good solubility of the alkylating reagent in the organic solvent. N (butyl) ₄ ⁺ -Cl ^-, N (butyl) ₄ ⁺ -HSO ₄ ^- not only N (methyl) ₄ ⁺ -Cl ^- also particularly preferred for use in the present invention.

  The end-protected polyethylene glycolic acid can also be produced in the same manner.

Formula (XI)

(Where L is

（式中、Ｓｇは、保護基を意味し、Ｌ、ＸおよびＲｆは、上記に示された意味を有する。）のアミンと反応している上記の親水性カルボン酸Ｒにより製造する。 Means. )
According to the amide formation methods known to those skilled in the art of the general formula (XII)

(Wherein Sg means a protecting group and L, X and Rf have the meanings indicated above) and is prepared from the above-mentioned hydrophilic carboxylic acid R which is reacted with the amine.

  Cleavage of the protecting group is according to methods known to those skilled in the art, for example hydrolysis, hydrogenolysis, alkali saponification of esters using alkali in aqueous alcohol at 0 ° C. to 50 ° C., mineral acid or eg tert-butyl In the case of esters, trifluoroacetic acid is used [Protective Groups in Organic Synthesis, 2nd Edition, T. et al. W. Greene and P.M. G. M.M. Wuts, John Wiley and Sons, Inc. New York, 1991], in the case of benzyl ether, carried out by acid saponification using hydrogen / palladium / carbon.

The compound of general formula (XII) is converted to general formula (XIII)

（Ｙ、Ｇ、ｓ、ｓ’およびζは上記に示された意味を有し、Ｎｕは、塩基および場合により相間移動触媒の存在下において脱離基を意味する。）の過フッ素含有求核剤を有する保護基を意味する。］のモノ保護ジアミンにより製造する。脱離基として、例えば基−Ｃｌ、−Ｂｒ、−Ｊ、−ＯＴｓ、−ＯＭｓ、−ＯＳＯ₂ＣＦ₃、−ＯＳＯ₂Ｃ₄Ｆ₉または−ＯＳＯ₂Ｃ₈Ｆ₁₇を、一般式ＸＶＩＩＩのアルキル化試薬中に含有することができる。 [Reacts with R ⁸ , R ^{8 ′} , n ′, W, and m ′ in the meanings indicated above, and Sg is represented by the general formula (XIV)

(Y, G, s, s ′ and ζ have the meanings indicated above, and Nu means a leaving group in the presence of a base and optionally a phase transfer catalyst.) It means a protecting group having an agent. ] With mono-protected diamine. As a leaving group, for example, a group —Cl, —Br, —J, —OTs, —OMs, —OSO ₂ CF ₃ , —OSO ₂ C ₄ F ₉ or —OSO ₂ C ₈ F ₁₇ can be substituted with an alkyl of the general formula XVIII. Can be contained in the reagent.

  Known perfluorinated nucleophiles of the general formula (XIV) as well as additional perfluoroalkyl-containing materials and their preparation are described in the following publications.

L is

［上記に示された意味のＸおよびＲ_fと反応し、
当業者に公知のアミド形成する方法に従い、一般式（ＸＶＩ）

（ｑ、βは、上記に示された意味であり、Ｓｇは、保護基を意味する。）
のアミンと反応する。］
の過フッ素含有カルボン酸により製造される。 (Q, α, β and γ have the meanings indicated above.)
The compound of the general formula (XI) means that the general formula (XV)

[Reacts with the meanings X and R _f shown above,
According to methods of amide formation known to those skilled in the art, the compound of general formula (XVI)

(Q and β are the meanings indicated above, and Sg is a protecting group.)
Reacts with amines. ]
Of perfluorinated carboxylic acids.

  Cleavage of the protecting group is according to methods known to those skilled in the art, for example hydrolysis, hydrogenolysis, alkali saponification of esters using alkali in aqueous alcohol at 0 ° C. to 50 ° C., mineral acid or eg tert-butyl In the case of esters, trifluoroacetic acid is used [Protective Groups in Organic Synthesis, 2nd Edition, T. et al. W. Greene and P.M. G. M.M. Wuts, John Wiley and Sons, Inc. , New York, 1991], in the case of benzyl ether, it is carried out by acid saponification using hydrogen / palladium / carbon.

  The preparation of the compound of general formula (XV) is described in the references cited above for the preparation of perfluorinated compounds.

（ｑ、βは、上記に示された意味であり、Ｓｇは保護基を意味する。）
の化合物を、当業者に公知のアミド形成する方法に従い、一般式（ＸＶＩＩ）

（ｑは、上記に示された意味であり、ＳｇおよびＳｇ’は、保護基を意味し、ＳｇおよびＳｇ’を異なる方法で切断することができる。）
のカルボン酸と反応している上記の親水性アミンＲにより製造される。 Formula (XVI)

(Q and β are the meanings indicated above, and Sg is a protecting group.)
In accordance with methods of amide formation known to those skilled in the art of general formula (XVII)

(Q is the meaning indicated above, Sg and Sg ′ mean protecting groups, and Sg and Sg ′ can be cleaved in different ways.)
Prepared by the above-mentioned hydrophilic amine R reacting with the carboxylic acid.

  Cleavage of the protecting group is according to methods known to those skilled in the art, for example hydrolysis, hydrogenolysis, alkali saponification of esters using alkali in aqueous alcohol at 0 ° C. to 50 ° C., mineral acid or eg tert-butyl In the case of esters, trifluoroacetic acid is used [Protective Groups in Organic Synthesis, 2nd Edition, T. et al. W. Greene and P.M. G. M.M. Wuts, John Wiley and Sons, Inc. New York, 1991], in the case of benzyl ether, carried out by acid saponification using hydrogen / palladium / carbon.

  Such 2x-protected amino acids of general formula (XVII) are commercial products (Bachem).

  The compounds in the present invention are particularly suitable for use in NMR and X-ray diagnostics, radiodiagnosis and radiotherapy, and MRT lymphography and blood pool images. Perfluoroalkyl-containing metal complexes allow visualization of various physiological and pathophysiological structures and hence improved diagnostic information such as disease location and extent, selection and monitoring of effective target treatments and diseases and disorders It is particularly suitable for use in nuclear spin resonance tomography (MRT) for prevention.

  In a particularly preferred embodiment, the substances according to the invention are used for MRT lymphography.

  In another particularly preferred embodiment, the substances according to the invention are used for blood pool images.

  Suitable diseases and disorders are tumor diseases, particularly primary tumor detection and characterization, hygiene metastasis, lymph node metastasis and necrosis, cardiovascular diseases, especially vascular changes such as stenosis and aneurysms, arteriosclerotic plaques Detection of arteriosclerosis, thromboembolic disease, infarction, necrosis, inflammation, especially arthritis, meningitis, ulcerative colitis and nerve damage.

  In a particularly preferred embodiment, the substances according to the invention are used for necrosis or tumor imaging.

  In addition, the test substance of the present invention is a pharmaceutical preparation containing at least one physiologically compatible compound of the present invention, optionally having additives commonly used in galenical preparations.

  The compounds of the invention are distinguished by excellent compatibility and at the same time excellent image properties. They are therefore particularly suitable for systemic use of MRT, in particular MRT lymphography and tumor imaging.

  The preparation of the pharmaceutical preparation according to the present invention is carried out by suspending or dissolving the complex compound according to the present invention in an aqueous mediator, which is a method known in the art, optionally adding additives generally used in galenical preparations. After the treatment, the suspension or solution is optionally sterilized. For example, suitable additives include physiologically harmless buffers (eg, tromethamine), complexing agents or weak complexes (eg, diethylenetriaminepentaacetic acid or Ca complexes corresponding to the metal complexes in the present invention) or, if necessary, There is the addition of an electrolyte such as sodium chloride or, if necessary, an antioxidant such as ascorbic acid.

  When a suspension or solution of the agent according to the invention in water or saline solution is required for enteral or parenteral administration or other purposes, one or more of the commonly used in galenical formulations Adjuvants (eg methylcellulose, lactose, mannitol) and / or surfactant (s) (eg lecithin, Tween®, Myrj®) and / or for taste correction ( Mix with one or more flavoring substances (eg essential oils).

  It is possible to produce the pharmaceutical preparation of the present invention mainly without isolating the complex. In some cases, special care must be taken to chelate in order to ensure that the complexes according to the invention are substantially free of toxic, uncomplexed metal ions.

  For example, this can be ensured by adjusting the titration during the manufacturing process using a colored indicator such as xylenol orange. Therefore, the present invention also relates to a method for producing a complex compound and a salt thereof. A final note is the purification of the isolated complex.

  For in-vivo administration of a drug in the present invention, the drug can be administered in conjunction with a suitable vehicle, such as serum or common saline solution, and in combination with other proteins, such as human serum albumin (HSA). .

  The medicament in the present invention is usually parenterally, preferably i. v. To administer. They can also be administered intravascularly, interstitial / intradermally depending on whether the body vessel (s) or tissues are examined.

  The pharmaceutical preparation in the present invention preferably contains 0.1 μmol to 2 mol / l of the complex, and is generally administered at a dose of 0.001 to 5 mmol / kg.

  The agent in the present invention satisfies many suitability requirements as a contrast agent for nuclear spin tomography. After oral or parenteral administration, they are therefore very suitable for enhancing the information value of images obtained from nuclear spin tomography by increasing the signal intensity. They also demonstrate the high effectiveness required to load the body with the smallest amount of foreign material possible and the good suitability required to maintain the non-invasive nature of the study.

  Due to the good water solubility and low osmotic pressure of the drug in the present invention, the production of a high concentration solution makes it possible to maintain the circulatory load within reasonable limits and offset the dilution with body fluids. Furthermore, the agents in the present invention not only show high stability in vitro but also surprisingly high stability in vivo, which is new in the release or exchange of inherently toxic, complex bound ions. This is because the contrast agent is carried out very slowly within the time when it is completely excreted again.

  Generally, in use as a diagnostic agent for NMR, the drug in the present invention is administered at 0.0001 to 5 mmol / kg, preferably 0.005 to 0.5 mmol / kg.

  The complex compound in the present invention can also be advantageously used as a sensitive reagent and shift reagent for in vivo NMR spectroscopy.

  Because of these advantageous radiation characteristics and the stability of the complex compounds contained therein, the agents in the present invention are also suitable as radiodiagnostic agents. Details of such uses and dosages are described, for example, in "Radiotracers for Medical Applications", CRC Press, Boca Raton, Florida.

Also, the compounds and agents in the present invention can be used for positron imaging, which uses positron emitting isotopes such as ⁴³ Sc, ⁴⁴ Sc, ⁵² Fe, ⁵⁵ Co, ⁶⁸ Ga and ⁸⁶ Y. (Heiss, WD ,; Phelps, ME; Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York 1983).

  Histological examination confirms the super permeability of local microvessels.

  Therefore, the contrast agent in the present invention can be used to visualize an abnormality in capillary permeability.

  The compounds in the present invention are mainly distinguished by their complete excretion from the body and therefore well tolerated. Thus, superior image characteristics can be used and maintain the non-invasive nature of the diagnosis.

Since the substances in the present invention accumulate in malignant tumors (which do not diffuse in healthy tissues but have high permeability of tumor tubes), they are also useful for radiodiagnosis of malignant tumors. Malignant tumors are distinguished by the diagnosis only by the amount and type of isotope used. In this case, the tumor cells are destroyed by high energy shortwave radiation with the smallest possible range of action. In this regard, the interaction of metals (eg ions or gadolinium) contained in complexes with ionizing radiation (eg x-rays) or neutron radiation is used. This effect significantly increases the local radiation dose at the site where the metal complex is found (eg within the tumor). While producing the same radiation dose in malignant tissue, radiation exposure in healthy tissue can be significantly reduced, thus avoiding bothersome side effects for patients when using such metal complexes. it can. Therefore, the metal complex conjugate in the present invention is also suitable as a radiosensitive substance in radiotherapy of malignant tumors (for example, in the case of using the Mossbauer effect or neutron capture therapy). For example, suitable β-emitting ions are ⁴⁶ Sc, ⁴⁷ Sc, ⁴⁸ Sc, ⁷² Ga, ⁷³ Ga and ⁹⁰ Y. For example, alpha-emitting ions that exhibit suitable short half-lives are ²¹¹ Bi, ²¹² Bi, ²¹³ Bi and ²¹⁴ Bi, with ²¹² Bi being preferred. A suitable photon and electron emitting ion is ¹⁵⁸ Gd, which can be obtained from ¹⁵⁷ Gd by neutron capture.

The drug in the present invention is R.I. L. Mills et al. [Nature Vol. 36, (1988), p. 787], the central ion must be derived from a Mössbauer isotope, such as ⁵⁷ Fe or ¹⁵¹ Eu.

  For in-vivo administration of a drug in the present invention, the drug can be administered in conjunction with a suitable vehicle, such as serum or common saline solution, and in combination with other proteins, such as human serum albumin. The dose in this case is determined by the type of cell disruption, the metal ions used and the type of imaging method.

  The medicament in the present invention is usually parenterally, preferably i. v. To administer. They can also be administered intravascularly, interstitial / intradermally, as described above, depending on whether the body blood vessel (s) or tissues are examined.

  The agent in the present invention is very suitable as an x-ray contrast agent, particularly emphasizing that the signs of anaphylactoid reaction known by iodine-containing contrast agents could not be detected in biochemical-pharmacological tests. These are particularly beneficial due to the advantageous absorption characteristics in the range of higher tube voltages in the digital subtraction method.

  In general, the agents according to the invention to be administered are used as x-ray contrast agents, for example as in meglumine-diatrizoate 0.1-5 mmol / kg, preferably 0.25-1 mmol / kg.

“Metal ion equivalent” as used in this application is a general term and is known to those skilled in the art of complex chemistry. The metal ion equivalent is, for example, the equivalent of a metal ion that can bind to a carboxylate group instead of hydrogen. For example, Gd ³⁺ can be attached to three carboxylate groups, ie when the metal is gadolinium, 1 / 3Gd ³⁺ is a metal of formula (II) (III) (IV) or (V) It corresponds to the ion equivalent R ¹ .

ｂ）Ｎ−［２−（ベンジルオキシカルボニル）−アミノエチル−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−［１−Ｏ−α−ｄ−（２，３，４，６−テトラ−Ｏ−ベンジル）マンノピラノシル］−アセトアミド
ジシクロヘキシルカルボジイミド８．０５ｇ（３９．０４ｍｍｏｌ）を実施例１ａの表題化合物２０ｇ（３１．２３ｍｍｏｌ）および１−Ｏ−α−ｄ−カルボニルメチル−（２，３，４，６−テトラ−Ｏ−ベンジル）マンノピラノース（ＷＯ９９／０１１６０Ａ１に従い製造）１８．７０ｇ（３１．２３ｍｍｏｌ）ならびにＮ−ヒドロキシスクシンイミド３．５９ｇ（３１．２３ｍｍｏｌ）のジメチルホルムアミド２００ｍｌ中溶液に０℃にて添加し、それを０℃にて３時間および次いで室温にて１６時間撹拌する。析出した尿素を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール２０：１）。
収率：無色、粘性油２９．８ｇ（理論値７８％）
元素分析：

ｃ）Ｎ−（２−アミノエチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−（１−Ｏ−α−ｄ−マンノピラノシル）−アセトアミド、メタンスルホン酸塩
メタンスルホン酸２．２９ｇ（２３．７５ｍｍｏｌ）およびパラジウム触媒（１０％Ｐｄ／Ｃ）４．０ｇを実施例１ｂの表題化合物２９ｇ（２３．７５ｍｍｏｌ）のエタノール５００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１９．５ｇ（定量）
元素分析：

ｄ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−アミノエチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−（１−Ｏ−α−ｄ−マンノピラノシル）−アセトアミド、Ｇｄ錯体
実施例１ｃの表題化合物１８．７ｇ（２２．７２ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド２．６１ｇ（２２．７２ｍｍｏｌ）、塩化リチウム１．９３ｇ（４５．４４ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン１４．３１ｇ（２２．７２ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド２００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド５．８６ｇ（２８．４ｍｍｏｌ）およびトリエチルアミン２．３０ｇ（２２．７２ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体２２．３ｇ（理論値６８％）
水分量（カール・フィッシャー法）：７．０％
元素分析（無水物質相対比）：

Example Example 1
a) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-aza-perfluorotridecylamine N-benzyloxycarbonyl-ethylenediamine (Atwell et al., Synthesis) , 1984, 1032-1033) 23.31 g (120 mmol) and 10.2 g (100 mmol) of triethylamine in 500 ml of acetonitrile. , 2000, 3291-3302) is added to 54.22 g (100 mmol) and it is stirred at 60 ° C. for 48 hours. Insoluble constituents are filtered off from the reaction solution, it is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: 32.8 g of colorless wax (theoretical value: 51%)
Elemental analysis:

b) N- [2- (benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- [1-O-α-d- (2,3,4,6) -Tetra-O-benzyl) mannopyranosyl] -acetamide 8.05 g (39.04 mmol) of dicyclohexylcarbodiimide and 20 g (31.23 mmol) of the title compound of Example 1a and 1-O-α-d-carbonylmethyl- (2,3 , 4,6-tetra-O-benzyl) mannopyranose (prepared according to WO99 / 01160A1) 18.70 g (31.23 mmol) and 3.59 g (31.23 mmol) of N-hydroxysuccinimide in a solution of 200 ml of dimethylformamide Add at 0 ° C. and stir it at 0 ° C. for 3 hours and then at room temperature for 16 hours The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, 29.8 g of viscous oil (theoretical 78%)
Elemental analysis:

c) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (1-O-α-d-mannopyranosyl) -acetamide, methanesulfonate methanesulfonic acid 2 .29 g (23.75 mmol) and 4.0 g of palladium catalyst (10% Pd / C) are added to a solution of 29 g (23.75 mmol) of the title compound of Example 1b in 500 ml of ethanol, which is hydrogenated at room temperature for 24 hours. Turn into. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 19.5 g of colorless solid (quantitative)
Elemental analysis:

d) N-{[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetracyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl -5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (1-O-α-d-mannopyranosyl) -acetamide, Gd complex of Example 1c 18.7 g (22.72 mmol) of the title compound, 2.61 g (22.72 mmol) of N-hydroxysuccinimide, 1.93 g (45.44 mmol) of lithium chloride and 1,4,7-tris- (carboxylatomethyl) -10 -[1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane (31.72 g) (22.72) Gd complex of mol) (WO98 / 24775, Schering AG, (Example 1) are dissolved in dimethyl sulfoxide 200ml with slight heating). At 10 ° C., 5.86 g (28.4 mmol) of dicyclohexylcarbodiimide and 2.30 g (22.72 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 22.3 g of colorless solid (theoretical value: 68%)
Moisture content (Karl Fischer method): 7.0%
Elemental analysis (anhydrous relative ratio):

ｂ）１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−Ｎ−［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−ペルフルオロトリデシルアミン、Ｇｄ錯体、メタンスルホン酸塩
メタンスルホン酸１．１６ｇ（１２．０８ｍｍｏｌ）およびパラジウム触媒（１０％Ｐｄ／Ｃ）２．０ｇを実施例２ａの表題化合物１６ｇ（１２．０８ｍｍｏｌ）のエタノール３００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１５．８ｇ（定量）
水分量（カール・フィッシャー法）：７．０％
元素分析（無水物質相対比）：

ｃ）１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−Ｎ−［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−ペルフルオロトリデシル−Ｎ−２−（１−Ｏ−α−ｄ−マンノピラノシル）−アセトアミド、Ｇｄ錯体
ジシクロヘキシルカルボジイミド１．７２ｇ（８．３３ｍｍｏｌ）およびトリエチルアミン６７４ｍｇ（６．６６ｍｍｏｌ）を実施例２ｂの表題化合物８．９ｇ（６．６６ｍｍｏｌ）および１−Ｏ−α−ｄ−カルボニルメチル−（２，３，４，６−テトラ−Ｏ−ベンジル）マンノピラノース（ＷＯ９９／０１１６０Ａ１に従い製造）３．９９ｇ（６．６６ｍｍｏｌ）ならびにＮ−ヒドロキシスクシンイミド７６７ｍｇ（６．６６ｍｍｏｌ）のジメチルホルムアミド１００ｍｌ中溶液に０℃にて添加する。それを０℃にて３時間および次いで室温にて１６時間撹拌する。析出した尿素を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。残留物をメタノール１００ｍｌに溶解し、パラジウム触媒（１０％Ｐｄ／Ｃ）２．０ｇと混合し、室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。残留物を少量の水に取り出し、不溶性の構成要素を濾過して取り除き、次いで濾液をクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体６．１ｇ（理論値６４％）
水分量（カール・フィッシャー法）：６．２％
元素分析（無水物質相対比）：

Example 2
a) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4 , 7,10-Tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-perfluorotridecylamine, Gd complex The title compound of Example 1a10. 0 g (15.62 mmol), 1.80 g (15.62 mmol) N-hydroxysuccinimide, 1.33 g (31.34 mmol) lithium chloride and 1,4,7-tris- (carboxylatomethyl) -10- [1- Carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane 9.84 g (15.62 mmol) Gd complex (WO 98/24775, Schering AG, (Example 1)) is dissolved in 150 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 4.03 g (19.52 mmol) of dicyclohexylcarbodiimide is added and it is stirred for 16 hours at room temperature. The solution is poured into 2000 ml of diethyl ether and stirred for more than 10 minutes. The precipitated solid is filtered and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / aqueous ammonia 10: 5: 1).
Yield: 16.4 g of colorless solid (theoretical value 79%)
Moisture content (Karl Fischer method): 5.4%
Elemental analysis (anhydrous relative ratio):

b) 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane- 10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-perfluorotridecylamine, Gd complex, methanesulfonate 1.16 g (12.08 mmol) methanesulfonic acid and palladium 2.0 g of catalyst (10% Pd / C) is added to a solution of 16 g (12.08 mmol) of the title compound of Example 2a in 300 ml of ethanol and it is hydrogenated at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 15.8 g of colorless solid (quantitative)
Moisture content (Karl Fischer method): 7.0%
Elemental analysis (anhydrous relative ratio):

c) 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane- 10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-perfluorotridecyl-N-2- (1-O-α-d-mannopyranosyl) -acetamide, Gd complex dicyclohexyl 1.72 g (8.33 mmol) of carbodiimide and 674 mg (6.66 mmol) of triethylamine were added to 8.9 g (6.66 mmol) of the title compound of Example 2b and 1-O-α-d-carbonylmethyl- (2,3,4 , 6-Tetra-O-benzyl) mannopyranose (prepared according to WO 99 / 01160A1) 3.99 g (6.66 mmol) and N-hydroxy In dimethylformamide 100ml solution of succinimide 767 mg (6.66 mmol) is added at 0 ° C.. It is stirred for 3 hours at 0 ° C. and then for 16 hours at room temperature. The precipitated urea is filtered off and the filtrate is evaporated to dryness under vacuum. The residue is dissolved in 100 ml of methanol, mixed with 2.0 g of palladium catalyst (10% Pd / C) and hydrogenated at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum. The residue is taken up in a little water, insoluble constituents are filtered off and the filtrate is then purified by chromatography (RP-18; mobile solvent: gradient consisting of water / acetonitrile).
Yield: 6.1 g of colorless solid (theoretical value 64%)
Water content (Karl Fischer method): 6.2%
Elemental analysis (anhydrous relative ratio):

ｂ）Ｎ−［２−（ベンジルオキシカルボニル）−アミノエチル−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−［１，３−ビス−（２−ベンジルオキシ−１−ベンジルオキシメチル−エトキシ）−プロプ−２−オキシ］−アセトアミド
ジシクロヘキシルカルボジイミド８．０５ｇ（３９．０４ｍｍｏｌ）を実施例１ａの表題化合物２０ｇ（３１．２３ｍｍｏｌ）および実施例３ａの表題化合物２０．５７ｇ（３１．２３ｍｍｏｌ）ならびにＮ−ヒドロキシスクシンイミド３．５９ｇ（３１．２３ｍｍｏｌ）のジメチルホルムアミド２００ｍｌ中溶液に０℃にて添加し、それを０℃にて３時間、次いで室温にて１６時間撹拌する。析出した尿素を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール２０：１）。
収率：無色、粘性油２８．７ｇ（理論値７２％）
元素分析：

ｃ）Ｎ−（２−アミノエチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−［１，３−ビス−（２−ヒドロキシ−１−ヒドロキシメチル−エトキシ）−プロプ−２−オキシ］−アセトアミド、メタンスルホン酸塩
メタンスルホン酸１．９６ｇ（２０．２９ｍｍｏｌ）およびパラジウム触媒（１０％Ｐｄ／Ｃ）４．０ｇを実施例３ｂの表題化合物２６ｇ（２０．２９ｍｍｏｌ）のエタノール５００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１７．９ｇ（定量）
元素分析：

ｄ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−アミノエチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−［１，３−ビス−（２−ヒドロキシ−１−ヒドロキシメチル−エトキシ）−プロプ−２−オキシ］−アセトアミド、Ｇｄ錯体
実施例３ｃの表題化合物１６．８ｇ（１９．０７ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド２．１９ｇ（１９．０７ｍｍｏｌ）、塩化リチウム１．６２ｇ（３８．１４ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン１４．１３ｇ（１９．０７ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド２００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド４．９２ｇ（２３．８４ｍｍｏｌ）およびトリエチルアミン１．９３ｇ（１９．０７ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体２０．６ｇ（理論値７２％）
水分量（カール・フィッシャー法）：６．７％
元素分析（無水物質相対比）：

Example 3
a) [1,3-Bis- (2-benzyloxy-1-benzyloxymethyl-ethoxy) -prop-2-yl] -acetic acid 14.62 g (75 mmol) of bromoacetic acid-tert-butyl ester in 250 ml of toluene , 3-bis- (2-benzyloxy-1-benzyloxymethyl-ethoxy) -propan-2-ol (Cassel et al., Eur. J. Org. Chem., 2001, 5, 875-896). 02 g (50 mmol) and 5.6 g (100 mmol) of finely powdered potassium hydroxide and a catalytic amount of tetra-n-butylammonium hydrogen sulfate (1 g) were added at 0 ° C. at this temperature for 2 hours and at room temperature. And stir for 12 hours. The reaction solution is mixed with 500 ml of ethyl acetate and 300 ml of water. The organic phase is separated, washed twice with 300 ml of water each time, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is suspended in a mixture consisting of 400 ml of 2: 1 methanol and 0.5 M sodium hydroxide solution and then heated at 60 ° C. for 12 hours. The reaction mixture is neutralized by mixing with Amberlite IR120 (H ⁺ form) -cation exchange resin for workup, the ion exchanger is filtered off, evaporated to dryness and subjected to silica gel chromatography (transfer) Solvent: ethyl acetate / hexane 1: 3).
Yield: 23.5 g of colorless wax (theoretical value 71%)
Elemental analysis:

b) N- [2- (benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- [1,3-bis- (2-benzyloxy-1-benzyloxy) Methyl-ethoxy) -prop-2-oxy] -acetamide 8.05 g (39.04 mmol) of dicyclohexylcarbodiimide was added to 20 g (31.23 mmol) of the title compound of Example 1a and 20.57 g (31.23 mmol) of the title compound of Example 3a. ) And 3.59 g (31.23 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide at 0 ° C. and it is stirred at 0 ° C. for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, viscous oil 28.7 g (theoretical 72%)
Elemental analysis:

c) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- [1,3-bis- (2-hydroxy-1-hydroxymethyl-ethoxy) -prop- 2-Oxy] -acetamide, methanesulfonate 1.96 g (20.29 mmol) of methanesulfonic acid and 4.0 g of palladium catalyst (10% Pd / C) were added to 26 g (20.29 mmol) of the title compound of Example 3b in ethanol. Add to solution in 500 ml and hydrogenate it at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 17.9 g of colorless solid (quantitative)
Elemental analysis:

d) N-{[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- [1,3-bis- (2-hydroxy-1-hydroxymethyl-ethoxy) -Prop-2-oxy] -acetamide, Gd complex 16.8 g (19.07 mmol) of the title compound of Example 3c, 2.19 g (19.07 mmol) of N-hydroxysuccinimide, 1.62 g (38.14 mmol) of lithium chloride And 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7 Gd complex (WO 98/24775, Schering AG, (Example 1)), which is 14.13 g (19.07 mmol), 10-tetraazacyclododecane, is dissolved in 200 ml dimethyl sulfoxide with slight heating. At 10 ° C., 4.92 g (23.84 mmol) of dicyclohexylcarbodiimide and 1.93 g (19.07 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 20.6 g of colorless solid (theoretical 72%)
Moisture content (Karl Fischer method): 6.7%
Elemental analysis (anhydrous relative ratio):

Example 4
a) 1,4,7- {Tris (carboxylatomethyl) -10 [(3-aza-4-oxo-hexane-5-yl} acid-N-1H, 1H, 2H, 2H, 4H, 4H, 5H , 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo- 5-methyl-5-yl)]-perfluorotridecylamide) -1,4,7,10-tetraazacyclododecane, Gd complex 8.1 g (6.31 mmol) of the title compound of Example 2b, N-hydroxysuccinimide 726 mg (6.31 mmol), 535 mg (12.62 mmol) lithium chloride and 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo Gd complex (WO98 / 24775, Schering AG, (Example 1)) which is 3.97 g (6.31 mmol) of -5, -methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane. Dissolve in 100 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 1.63 g (7.89 mmol) of dicyclohexylcarbodiimide and 693 mg (6.31 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 6.5 g of colorless solid (theoretical value: 56%)
Moisture content (Karl Fischer method): 5.8%
Elemental analysis (anhydrous relative ratio):

ｂ）Ｎ−（２−アミノエチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−［２−（２−メトキシエトキシ）−エトキシ］−アセトアミド、メタンスルホン酸塩
メタンスルホン酸２．２８ｇ（２３．７３ｍｍｏｌ）およびパラジウム触媒（１０％Ｐｄ／Ｃ）４．０ｇを実施例５ａの表題化合物１９ｇ（２３．７３ｍｍｏｌ）のエタノール５００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１８．１ｇ（定量）
元素分析：

ｃ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−アミノエチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−［２−（２−メトキシエトキシ）−エトキシ］−アセトアミド、Ｇｄ錯体
実施例５ｂの表題化合物１７．２ｇ（２２．５１ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド２．５９ｍｇ（２２．５１ｍｍｏｌ）、塩化リチウム１．９１ｇ（４５．０２ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン１４．１８ｇ（２２．５１ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド２００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド５．８１ｇ（２８．１４ｍｍｏｌ）およびトリエチルアミン２．２８ｇ（２２．５１ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体２１．５ｇ（理論値７０％）
水分量（カール・フィッシャー法）：６．４％
元素分析（無水物質相対比）：

Example 5
a) N- [2- (Benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- [2- (2-methoxyethoxy) -ethoxy] -acetamide dicyclohexylcarbodiimide 8 0.05 g (39.04 mmol) of the title compound of Example 1a 20 g (31.23 mmol) and [2- (2-methoxyethoxy) -ethoxy] -acetic acid (Aldrich) 5.57 g (31.23 mmol) and N-hydroxy To a solution of 3.59 mg (31.23 mmol) of succinimide in 200 ml of dimethylformamide is added at 0 ° C. and it is stirred for 3 hours at 0 ° C. and then for 16 hours at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, 19.8 g of viscous oil (theoretical value 79%)
Elemental analysis:

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- [2- (2-methoxyethoxy) -ethoxy] -acetamide, methanesulfonate methanesulfonic acid 2.28 g (23.73 mmol) and 4.0 g of palladium catalyst (10% Pd / C) were added to a solution of 19 g (23.73 mmol) of the title compound of Example 5a in 500 ml of ethanol, which was allowed to reach room temperature for 24 hours. Hydrogenate. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 18.1 g of colorless solid (quantitative)
Elemental analysis:

c) N-{[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- [2- (2-methoxyethoxy) -ethoxy] -acetamide, Gd complex Examples 5b title compound 17.2 g (22.51 mmol), N-hydroxysuccinimide 2.59 mg (22.51 mmol), lithium chloride 1.91 g (45.02 mmol) and 1,4,7-tris- (carboxylatomethyl) -10- [1-Carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane 14.18 g The Gd complex (WO 98/24775, Schering AG, (Example 1)) which is (22.51 mmol) is dissolved in 200 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 5.81 g (28.14 mmol) of dicyclohexylcarbodiimide and 2.28 g (22.51 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP18; mobile solvent: gradient consisting of water / acetonitrile).
Yield: 21.5 g of colorless solid (theoretical value 70%)
Moisture content (Karl Fischer method): 6.4%
Elemental analysis (anhydrous relative ratio):

ｂ）１−Ｎ−（ベンジルオキシカルボニル）−１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ，７Ｈ，７Ｈ，８Ｈ，８Ｈ−３−アザ−６−オキソ−ペルフルオロヘキサデシルアミン
ＴＨＦ１５０ｍｌ中実施例６ａの表題化合物４８．５ｇ（６９．４５ｍｍｏｌ）を（ＴＨＦ中）１０Ｍボランジメチルスルフィド５０ｍｌと混合し、５時間還流する。それを０℃に冷却し、メタノール１００ｍｌを滴下にて添加し、それを室温にて１時間撹拌後、真空下において、乾燥状態に蒸発させる。残留物をエタノール３００ｍｌ／１Ｍ塩酸５０ｍｌからなる混合物に取り出し、それを４０℃にて１４時間撹拌する。真空下において、それを乾燥状態に蒸発させ、残留物を５％水酸化ナトリウム溶液３００ｍｌに取り出し、ジクロロメタン各３００ｍｌで３回抽出する。混合した有機相を硫酸マグネシウムで乾燥させ、真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール１０：１）。
収率：無色固体３９．８ｇ（理論値８４％）
元素分析：

ｃ）Ｎ−［２−（ベンジルオキシカルボニル）−アミノエチル−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−オキサ−ペルフルオロトリデシル）−２−［２−（２−メトキシエトキシ）−エトキシ］−アセトアミド
ジシクロヘキシルカルボジイミド７．５４ｇ（３６．５３ｍｍｏｌ）を実施例６ｂの表題化合物２０ｇ（２９．２２ｍｍｏｌ）および［２−（２−メトキシエトキシ）−エトキシ］−酢酸（Ａｌｄｒｉｃｈ）５．２１ｇ（２９．２２ｍｍｏｌ）ならびにＮ−ヒドロキシスクシンイミド３．３６ｍｇ（２９．２２ｍｍｏｌ）のジメチルホルムアミド２００ｍｌ中溶液に０℃にて添加し、それを０℃にて３時間および次いで室温にて１６時間撹拌する。析出した尿素を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール２０：１）。
収率：無色、粘性油１８．３ｇ（理論値７４％）
元素分析：

ｄ）Ｎ−（２−アミノエチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−オキサ−ペルフルオロトリデシル）−２−［２−（２−メトキシエトキシ）−エトキシ］−アセトアミド、メタンスルホン酸塩
メタンスルホン酸２．０ｇ（２０．７２ｍｍｏｌ）およびパラジウム触媒（１０％Ｐｄ／Ｃ）３．０ｇを実施例６ｃの表題化合物１７．５ｇ（２０．７２ｍｍｏｌ）のエタノール３００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１６．７ｇ（定量）
元素分析：

ｅ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−アミノエチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−オキサ−ペルフルオロトリデシル）−２−［２−（２−メトキシエトキシ）−エトキシ］−アセトアミド、Ｇｄ錯体
実施例６ｄの表題化合物１４．８ｇ（１８．３０ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド２．１１ｍｇ（１８．３０ｍｍｏｌ）、塩化リチウム１．５５ｍｇ（３６．６０ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン１１．５２ｇ（１８．３０ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド２００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド４．７２ｇ（２２．８８ｍｍｏｌ）およびトリエチルアミン１．８５ｇ（１８．３０ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１６．６ｇ（理論値６４％）
水分量（カール・フィッシャー法）：６．９％
元素分析（無水物質相対比）：

Example 6
a) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 5H, 5H, 7H, 7H, 8H, 8H-3-aza-4-oxa-6-oxo-perfluorohexadecylamine oxalyl chloride 17.8 g (140 mmol) is added to 52.22 g (100 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid (prepared according to EP 01/08498) in 500 ml of dichloromethane and it is added at room temperature. For 14 hours. Under vacuum it was evaporated to dryness, the residue was dissolved in 400 ml dichloromethane and 23.31 g N-benzyloxycarbonyl-ethylenediamine (Atwell et al., Synthesis, 1984, 1032-1033) at 0 ° C. 120 mmol) and 10.2 g (100 mmol) of triethylamine and it is stirred for more than 24 hours at room temperature. The reaction solution is mixed with 400 ml of 1N hydrochloric acid and stirred thoroughly for 15 minutes. The organic phase is separated off, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate / hexane 1: 2).
Yield: 49.7 g of colorless wax (theoretical value 71%)
Elemental analysis:

b) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H, 7H, 7H, 8H, 8H-3-aza-6-oxo-perfluorohexadecylamine in 150 ml of THF 48.5 g (69.45 mmol) of the title compound of example 6a are mixed with 50 ml of 10M borane dimethyl sulfide (in THF) and refluxed for 5 hours. It is cooled to 0 ° C., 100 ml of methanol are added dropwise, it is stirred for 1 hour at room temperature and then evaporated to dryness under vacuum. The residue is taken up in a mixture consisting of 300 ml of ethanol / 50 ml of 1M hydrochloric acid and stirred at 40 ° C. for 14 hours. Under vacuum, it is evaporated to dryness, the residue is taken up in 300 ml of 5% sodium hydroxide solution and extracted three times with 300 ml of dichloromethane each. The combined organic phases are dried over magnesium sulfate, evaporated to dryness under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 10: 1).
Yield: 39.8 g of colorless solid (theoretical 84%)
Elemental analysis:

c) N- [2- (Benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -2- [2- ( 2-methoxyethoxy) -ethoxy] -acetamide 7.54 g (36.53 mmol) of dicyclohexylcarbodiimide was added to 20 g (29.22 mmol) of the title compound of Example 6b and [2- (2-methoxyethoxy) -ethoxy] -acetic acid (Aldrich). ) 5.21 g (29.22 mmol) and 3.36 mg (29.22 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide at 0 ° C. and added at 0 ° C. for 3 hours and then at room temperature. Stir for hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, viscous oil 18.3 g (theoretical 74%)
Elemental analysis:

d) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -2- [2- (2-methoxyethoxy) -Ethoxy] -acetamide, methanesulfonate 2.0 g (20.72 mmol) of methanesulfonic acid and 3.0 g of palladium catalyst (10% Pd / C) of 17.5 g (20.72 mmol) of the title compound of Example 6c Add to a solution in 300 ml of ethanol and hydrogenate it at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 16.7 g of colorless solid (quantitative)
Elemental analysis:

e) N-{[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -2- [2- (2- Methoxyethoxy) -ethoxy] -acetamide, Gd complex 14.8 g (18.30 mmol) of the title compound of Example 6d, 2.11 mg (18.30 mmol) of N-hydroxysuccinimide, 1.55 mg (36.60 mmol) of lithium chloride and 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7, Gd complex (WO 98/24775, Schering AG, (Example 1)), which is 11.52 g (18.30 mmol) of 10-tetraazacyclododecane, is dissolved in 200 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 4.72 g (22.88 mmol) of dicyclohexylcarbodiimide and 1.85 g (18.30 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 16.6 g of colorless solid (theoretical value 64%)
Moisture content (Karl Fischer method): 6.9%
Elemental analysis (anhydrous relative ratio):

ｂ）［１−Ｏ−α−ｄ−（２，３，４，６−テトラ−Ｏ−ベンジル）マンノピラノシル］−アセトアミド
塩化オキサリル１１．４５ｇ（９０ｍｍｏｌ）をジクロロメタン３００ｍｌ中１−Ｏ−α−ｄ−カルボニルメチル−（２，３，４，６−テトラ−Ｏ−ベンジル）マンノピラノース（ＷＯ９９／０１１６０Ａ１に従い製造）４０ｇ（６６．８１ｍｍｏｌ）に添加し、それを室温にて１４時間撹拌する。真空下において、それを乾燥状態に蒸発させ、残留物をジクロロメタン４００ｍｌに溶解し、アンモニアガスを０℃にて約２時間溶液に導入し、それを室温にて４時間以上撹拌する。反応溶液を１Ｎ塩酸４００ｍｌと混合し、それを１５分間完全に撹拌する。有機相を分離し、硫酸マグネシウムで乾燥し、真空下において、乾燥状態に蒸発させる。残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：酢酸エチル／ヘキサン１：２）。
収率：無色油３４．１ｇ（理論値８５％）
元素分析：

ｃ）２−［１−Ｏ−α−ｄ−（２，３，４，６−テトラ−Ｏ−ベンジル）マンノピラノシル］−エチルアミン
ＴＨＦ１００ｍｌ中実施例７ｂの表題化合物３３ｇ（５５．２１ｍｍｏｌ）を（ＴＨＦ中）１０Ｍボランジメチルスルフィド３０ｍｌと混合し、５時間還流する。それを０℃に冷却し、メタノール１００ｍｌを滴下にて添加し、それを室温にて１時間撹拌後、真空下において、乾燥状態に蒸発させる。残留物をエタノール２００ｍｌ／エタノールアミン１００ｍｌからなる混合物に取り出し、６０℃にて１４時間撹拌する。真空下において、それを乾燥状態に蒸発させ、残留物を５％水酸化ナトリウム溶液３００ｍｌに取り出し、それをジクロロメタン各３００ｍｌで３回抽出する。混合した有機相を硫酸マグネシウムで乾燥させ、真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール１０：１）。
収率：無色固体２６．２ｇ（理論値８１％）
元素分析：

ｄ）６−Ｎ−ベンジルオキシカルボニル−２−Ｎ−（２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−オキサペルフルオロトリデカノイル）−Ｌ−リジン−｛２−［１−Ｏ−α−ｄ−（２，３，４，６−テトラ−Ｏ−ベンジル）マンノピラノシル］−エチル｝−アミド
ジシクロヘキシルカルボジイミド４．９３ｇ（２３．９０ｍｍｏｌ）を実施例７ａの表題化合物１５ｇ（１９．１２ｍｍｏｌ）および実施例７ｃの表題化合物１１．１６ｇ（１９．１２ｍｍｏｌ）ならびにＮ−ヒドロキシスクシンイミド２．２０ｇ（１９．１２ｍｍｏｌ）のジメチルホルムアミド２００ｍｌ中溶液に０℃にて添加し、それを０℃にて３時間および次いで室温にて１６時間撹拌する。析出した尿素を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール２０：１）。
収率：無色、粘性油１９．２ｇ（理論値７４％）
元素分析：

ｅ）２−Ｎ−（２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−オキサペルフルオロトリデカニル）−Ｌ−リジン−［２−｛１−Ｏ−α−ｄ−（マンノピラノシル）−エチル］−アミド
パラジウム触媒（１０％Ｐｄ／Ｃ）２．０ｇを実施例７ｄの表題化合物１８．５ｇ（１３．７０ｍｍｏｌ）のエタノール２００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１１．８ｇ（定量）
元素分析：

ｆ）６−Ｎ−［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−Ｎ−（２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−オキサペルフルオロトリデカノイル）−Ｌ−リジン−［２−｛１−Ｏ−α−ｄ−マンノピラノシル）−エチル］−アミド、Ｇｄ錯体
実施例７ｅの表題化合物１１．０ｇ（１２．８６ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド１．４８ｇ（１２．８６ｍｍｏｌ）、塩化リチウム１．０９ｇ（２５．７２ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン８．１０ｇ（１２．８６ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド１００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド３．３２ｇ（１６．０８ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１３．０ｇ（理論値６４％）
水分量（カール・フィッシャー法）：６．９％
元素分析（無水物質相対比）：

Example 7
a) 6-N-benzyloxycarbonyl-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) -L-lysine 6-N-benzyloxycarbonyl-2-N -(2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) -L-lysine methyl ester (prepared according to EP03 / 07274) 25 g (31.31 mmol) in methanol 200 ml and 2N potassium hydroxide solution Dissolve in 50 ml and stir at room temperature for 18 hours. It is acidified with 2N hydrochloric acid, evaporated to dryness and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 10: 1).
Yield: 22.4 g of colorless solid (theoretical value: 91%)
Elemental analysis:

b) [1-O-α-d- (2,3,4,6-tetra-O-benzyl) mannopyranosyl] -acetamide 11.45 g (90 mmol) of oxalyl chloride in 1-O-α-d- Add to 40 g (66.81 mmol) of carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose (prepared according to WO99 / 01160A1) and stir it at room temperature for 14 hours. Under vacuum, it is evaporated to dryness, the residue is dissolved in 400 ml of dichloromethane, ammonia gas is introduced into the solution at 0 ° C. for about 2 hours and it is stirred at room temperature for more than 4 hours. The reaction solution is mixed with 400 ml of 1N hydrochloric acid and it is stirred thoroughly for 15 minutes. The organic phase is separated off, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate / hexane 1: 2).
Yield: 34.1 g of colorless oil (theoretical value: 85%)
Elemental analysis:

c) 2- [1-O-α-d- (2,3,4,6-tetra-O-benzyl) mannopyranosyl] -ethylamine 33 g (55.21 mmol) of the title compound of Example 7b in 100 ml of THF (in THF) ) Mix with 30 ml of 10M borane dimethyl sulfide and reflux for 5 hours. It is cooled to 0 ° C., 100 ml of methanol are added dropwise, it is stirred for 1 hour at room temperature and then evaporated to dryness under vacuum. The residue is taken up in a mixture of 200 ml ethanol / 100 ml ethanolamine and stirred at 60 ° C. for 14 hours. Under vacuum, it is evaporated to the dry state, the residue is taken up in 300 ml of 5% sodium hydroxide solution and it is extracted three times with 300 ml of dichloromethane each. The combined organic phases are dried over magnesium sulfate, evaporated to dryness under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 10: 1).
Yield: 26.2 g of colorless solid (theoretical value: 81%)
Elemental analysis:

d) 6-N-benzyloxycarbonyl-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) -L-lysine- {2- [1-O-α- d- (2,3,4,6-Tetra-O-benzyl) mannopyranosyl] -ethyl} -amide 4.93 g (23.90 mmol) of dicyclohexylcarbodiimide and 15 g (19.12 mmol) of the title compound of Example 7a and Example To a solution of 11.16 g (19.12 mmol) of the title compound of 7c and 2.20 g (19.12 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide at 0 ° C. is added at 0 ° C. for 3 hours and then at room temperature. For 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, 19.2 g of viscous oil (theoretical 74%)
Elemental analysis:

e) 2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanyl) -L-lysine- [2- {1-O-α-d- (mannopyranosyl) -ethyl] -Amide Palladium catalyst (10% Pd / C) 2.0 g is added to a solution of 18.5 g (13.70 mmol) of the title compound of example 7d in 200 ml of ethanol and it is hydrogenated at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 11.8 g of colorless solid (quantitative)
Elemental analysis:

f) 6-N- [1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5 -Methyl-5-yl)]-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) -L-lysine- [2- {1-O-α-d -Mannopyranosyl) -ethyl] -amide, Gd complex The title compound of Example 7e 11.0 g (12.86 mmol), N-hydroxysuccinimide 1.48 g (12.86 mmol), lithium chloride 1.09 g (25.72 mmol) and 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraaza Kurododekan 8.10 g Gd complex of (12.86mmol) (WO98 / 24775, Schering AG, (Example 1)) are dissolved in dimethyl sulfoxide 100ml with slight heating. At 10 ° C., 3.32 g (16.08 mmol) of dicyclohexylcarbodiimide is added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 13.0 g of colorless solid (theoretical value 64%)
Moisture content (Karl Fischer method): 6.9%
Elemental analysis (anhydrous relative ratio):

ｂ）２−Ｎ−（２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−オキサペルフルオロトリデカノイル）−Ｌ−リジン−｛［Ｎ−（２Ｓ，３Ｒ，４Ｒ，５Ｒ）−２，３，４，５，６−ペンタヒドロキシヘキシル］−Ｎ−メチル｝−アミド
パラジウム触媒（１０％Ｐｄ／Ｃ）１．０ｇを実施例８ａの表題化合物９．０ｇ（９．３９ｍｍｏｌ）のエタノール１００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体７．８ｇ（定量）
元素分析：

ｃ）６−Ｎ−［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−Ｎ−（２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−オキサペルフルオロトリデシカノイル）−Ｌ−リジン−｛［Ｎ−（２Ｓ，３Ｒ，４Ｒ，５Ｒ）−２，３，４，５，６−ペンタヒドロキシヘキシル］−Ｎ−メチル｝−アミド、Ｇｄ錯体
実施例８ｂの表題化合物７．０ｇ（８．４６ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド９７４ｍｇ（８．４６ｍｍｏｌ）、塩化リチウム７１７ｍｇ（１６．９２ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン５．３３ｇ（８．４６ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド１００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド２．１８ｇ（１０．５７ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体７．４ｇ（理論値５７％）
水分量（カール・フィッシャー法）：６．１％
元素分析（無水物質相対比）：

Example 8
a) 6-N-benzyloxycarbonyl-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) -L-lysine-{[N- (2S, 3R, 4R , 5R) -2,3,4,5,6-pentahydroxyhexyl] -N-methyl} -amide 4.93 g (23.90 mmol) of dicyclohexylcarbodiimide was added to 15 g (19.12 mmol) of the title compound of Example 7a and N -To a solution of 5.6 g (28.68 mmol) of methylglucamine (Aldrich) and 2.20 mg (19.12 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide at 0 ° C, it was added at 0 ° C for 3 hours. And then stirred at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 5: 1).
Yield: colorless, viscous oil 9.4 g (theoretical 51%)
Elemental analysis:

b) 2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) -L-lysine-{[N- (2S, 3R, 4R, 5R) -2,3 4,5,6-pentahydroxyhexyl] -N-methyl} -amide 1.0 g of palladium catalyst (10% Pd / C) was added to a solution of 9.0 g (9.39 mmol) of the title compound of Example 8a in 100 ml of ethanol. Add and hydrogenate it at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 7.8 g of colorless solid (quantitative)
Elemental analysis:

c) 6-N- [1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5 -Methyl-5-yl)]-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) -L-lysine-{[N- (2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxyhexyl] -N-methyl} -amide, Gd complex 7.0 g (8.46 mmol) of the title compound of Example 8b, 974 mg of N-hydroxysuccinimide (8. 46 mmol), 717 mg (16.92 mmol) of lithium chloride and 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentane- Gyl complex (WO98 / 24775, Schering AG, (Example 1)) which is 5.33 g (8.46 mmol) of 5-yl] -1,4,7,10-tetraazacyclododecane is heated with slight dimethyl Dissolve in 100 ml of sulfoxide. At 10 ° C., 2.18 g (10.57 mmol) of dicyclohexylcarbodiimide are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 7.4 g of colorless solid (theoretical value: 57%)
Water content (Karl Fischer method): 6.1%
Elemental analysis (anhydrous relative ratio):

ｂ）２−Ｎ−（２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−オキサペルフルオロトリデカノイル）−Ｌ−リジン−（２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−エチル）−アミド
パラジウム触媒（１０％Ｐｄ／Ｃ）１．０ｇを実施例９ａの表題化合物１１．５ｇ（１１．８１ｍｍｏｌ）のエタノール１００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体９．９５ｇ（定量）
元素分析：

ｃ）６−Ｎ−［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−Ｎ−（２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−オキサペルフルオロトリデカノイル）−Ｌ−リジン−（２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−エチル）−アミド、Ｇｄ錯体
実施例９ｂの表題化合物９．０ｇ（１０．７２ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド１．２３ｇ（１０．７２ｍｍｏｌ）、塩化リチウム９０９ｍｇ（２１．４４ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン６．７５ｇ（１０．７２ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド１００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド２．７６ｇ（１３．４ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１０．１ｇ（理論値６２％）
水分量（カール・フィッシャー法）：６．０％
元素分析（無水物質相対比）：

Example 9
a) 6-N-benzyloxycarbonyl-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) -L-lysine- (2- {2- [2- ( 2-methoxyethoxy) -ethoxy] -ethoxy} -ethyl) -amide 4.93 g (23.90 mmol) of dicyclohexylcarbodiimide was added to 15 g (19.12 mmol) of the title compound of Example 7a and (2- {2- [2- ( 2-methoxyethoxy) -ethoxy] -ethoxy} -ethyl) -amine (Whitesides et al., JACS, 1994, 5057-5062) 3.97 g (19.12 mmol) and N-hydroxysuccinimide 2.20 g (19.12 mmol) ) In 200 ml of dimethylformamide at 0 ° C. 3 hours and then for 16 hours at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 10: 1).
Yield: colorless, viscous oil 12.2 g (theoretical value 82%)
Elemental analysis:

b) 2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) -L-lysine- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -Ethoxy} -ethyl) -amide 1.0 g of palladium catalyst (10% Pd / C) was added to a solution of 11.5 g (11.81 mmol) of the title compound of Example 9a in 100 ml of ethanol at room temperature. Hydrogenate for hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 9.95 g of colorless solid (quantitative)
Elemental analysis:

c) 6-N- [1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5 -Methyl-5-yl)]-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecanoyl) -L-lysine- (2- {2- [2- (2 -Methoxyethoxy) -ethoxy] -ethoxy} -ethyl) -amide, Gd complex 9.0 g (10.72 mmol) of the title compound of Example 9b, 1.23 g (10.72 mmol) of N-hydroxysuccinimide, 909 mg of lithium chloride ( 21.44 mmol) and 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4 , 7,10-tetraazacyclododecane Gd complex (WO 98/24775, Schering AG, (Example 1)), which is 6.75 g (10.72 mmol), is dissolved in 100 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 2.76 g (13.4 mmol) of dicyclohexylcarbodiimide is added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 10.1 g of colorless solid (theoretical 62%)
Moisture content (Karl Fischer method): 6.0%
Elemental analysis (anhydrous relative ratio):

ｂ）１−Ｎ−（ベンジルオキシカルボニル）−１Ｈ，１Ｈ，２Ｈ，２Ｈ，５Ｈ，５Ｈ，７Ｈ，７Ｈ−３−アザ−４−オキサ−６−オキソ−ペルフルオロペンチルデシルアミン
塩化オキサリル１７．８ｇ（１４０ｍｍｏｌ）をジクロロメタン５００ｍｌ中実施例１０ａの表題化合物５０．８１ｇ（１００ｍｍｏｌ）に添加し、それを室温にて１４時間撹拌する。真空下において、それを乾燥状態に蒸発させ、残留物をジクロロメタン４００ｍｌに溶解し、０℃にてＮ−ベンジルオキシカルボニル−エチレンジアミン（Ａｔｗｅｌｌ ｅｔ ａｌ．，Ｓｙｎｔｈｅｓｉｓ，１９８４，１０３２−１０３３）２３．３１ｇ（１２０ｍｍｏｌ）およびトリエチルアミン１０．２ｇ（１００ｍｍｏｌ）と混合し、室温にて２４時間以上撹拌する。反応溶液を１Ｎ塩酸４００ｍｌと混合し、１５分間完全に撹拌する。有機相を分離し、硫酸マグネシウムで乾燥し、真空下において、乾燥状態に蒸発させる。残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：酢酸エチル／ヘキサン１：２）。
収率：無色ワックス４６．５ｇ（理論値６８％）
元素分析：

ｃ）１−Ｎ−（ベンジルオキシカルボニル）−１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ，７Ｈ，７Ｈ−３−アザ−６−オキソ−ペルフルオロペンタデシルアミン
ＴＨＦ１５０ｍｌ中実施例１０ｂの表題化合物４５．５ｇ（６６．４０ｍｍｏｌ）を（ＴＨＦ中）１０Ｍボランジメチルスルフィド５０ｍｌと混合し、５時間還流する。それを０℃に冷却し、メタノール１００ｍｌを滴下にて添加し、それを室温にて１時間撹拌後、真空下において、乾燥状態に蒸発させる。残留物をエタノール３００ｍｌ／１Ｍ塩酸５０ｍｌからなる混合物に取り出し、４０℃にて１４時間撹拌する。真空下において、それを乾燥状態に蒸発させ、残留物を５％水酸化ナトリウム溶液３００ｍｌに取り出し、ジクロロメタン各３００ｍｌで３回抽出する。混合した有機相を硫酸マグネシウムで乾燥させ、真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール１０：１）。
収率：無色固体３５．２ｇ（理論値７９％）
元素分析：

ｄ）Ｎ−［２−（ベンジルオキシカルボニル）−アミノエチル−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ−３−オキサ−ペルフルオロドデセニル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド
ジシクロヘキシルカルボジイミド７．６９ｇ（３７．２９ｍｍｏｌ）を実施例１０ｃの表題化合物２０ｇ（２９．８３ｍｍｏｌ）および｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ］−酢酸（Ｖｏｅｇｔｌｅ ｅｔ ａｌ．，Ｌｉｅｂｉｇｓ Ａｎｎ．Ｃｈｅｍ．，１９８０，８５８−８６２）６．６３ｍｇ（２９．８３ｍｍｏｌ）ならびにＮ−ヒドロキシスクシンイミド３．４３ｍｇ（２９．８３ｍｍｏｌ）のジメチルホルムアミド２００ｍｌ中溶液に０℃にて添加し、それを０℃にて３時間および次いで室温にて１６時間撹拌する。析出した尿素を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール２０：１）。
収率：無色、粘性油２０．１ｇ（理論値７７％）
元素分析：

ｅ）Ｎ−（２−アミノエチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ−３−オキサ−ペルフルオロドデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド、メタンスルホン酸塩
メタンスルホン酸２．０９ｇ（２１．７２ｍｍｏｌ）およびパラジウム触媒（１０％Ｐｄ／Ｃ）３．０ｇを実施例１０ｄの表題化合物１９．０ｇ（２１．７２ｍｍｏｌ）のエタノール３００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過し、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１８．２ｇ（定量）
元素分析：

ｆ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−アミノエチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ，−３−オキサ−ペルフルオロドデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド、Ｇｄ錯体
実施例１０ｅの表題化合物１５．８ｇ（１８．９ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド２．１８ｇ（１８．９ｍｍｏｌ）、塩化リチウム１．６０ｇ（３７．８０ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン１１．９０ｇ（１８．３０ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド２００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド４．８７ｇ（２３．６３ｍｍｏｌ）およびトリエチルアミン１．９１ｇ（１８．９ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１６．７ｇ（理論値６１％）
水分量（カール・フィッシャー法）：６．９％
元素分析（無水物質相対比）：

Example 10
a) 2H, 2H, 4H, 4H, 3-oxa-perfluorododecanoic acid 64.96 g (333.26 mmol) of bromoacetic acid-tert-butyl ester in 100 ml of 1H, 1H-perfluoro-1-nonanol (Apollo) in 800 ml of toluene ( 222.17 mmol) and 24.9 g (444 mmol) of finely powdered potassium hydroxide and a catalytic amount of tetra-n-butylammonium hydrogen sulfate (2 g) at 0 ° C., at this temperature for 2 hours and at room temperature for 12 hours. Stir for hours. The reaction solution is mixed with 1500 ml of ethyl acetate and 800 ml of water. After separating the organic phase and washing twice with 500 ml of water each, it is dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is suspended in a mixture consisting of 1200 ml of 2: 1 methanol and 0.5 M sodium hydroxide solution and then heated at 60 ° C. for 12 hours. The reaction mixture is neutralized by mixing with Amberlite IR120 (H ⁺ form) -cation exchange resin for workup, the ion exchanger is filtered, it is evaporated to dryness and subjected to silica gel chromatography (transfer) Solvent: ethyl acetate / hexane 1: 3).
Yield: 87 g of colorless wax (theoretical 77%)
Elemental analysis:

b) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 5H, 5H, 7H, 7H-3-aza-4-oxa-6-oxo-perfluoropentyldecylamine 17.8 g of oxalyl chloride ( 140 mmol) is added to 50.81 g (100 mmol) of the title compound of example 10a in 500 ml of dichloromethane and it is stirred at room temperature for 14 hours. Under vacuum, it was evaporated to dryness, the residue was dissolved in 400 ml of dichloromethane and 23.31 g of N-benzyloxycarbonyl-ethylenediamine (Atwell et al., Synthesis, 1984, 1032-1033) at 0 ° C. 120 mmol) and 10.2 g (100 mmol) of triethylamine and stirred at room temperature for at least 24 hours. The reaction solution is mixed with 400 ml of 1N hydrochloric acid and stirred thoroughly for 15 minutes. The organic phase is separated off, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate / hexane 1: 2).
Yield: 46.5 g of colorless wax (theoretical value: 68%)
Elemental analysis:

c) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H, 7H, 7H-3-aza-6-oxo-perfluoropentadecylamine Example 150b in 150 ml of THF 45.5 g (66.40 mmol) of the title compound is mixed with 50 ml of 10M borane dimethyl sulfide (in THF) and refluxed for 5 hours. It is cooled to 0 ° C., 100 ml of methanol are added dropwise, it is stirred for 1 hour at room temperature and then evaporated to dryness under vacuum. The residue is taken up in a mixture consisting of 300 ml of ethanol / 50 ml of 1M hydrochloric acid and stirred at 40 ° C. for 14 hours. Under vacuum, it is evaporated to dryness, the residue is taken up in 300 ml of 5% sodium hydroxide solution and extracted three times with 300 ml of dichloromethane each. The combined organic phases are dried over magnesium sulfate, evaporated to dryness under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 10: 1).
Yield: 35.2 g of colorless solid (theoretical value: 79%)
Elemental analysis:

d) N- [2- (benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H, 4H, 4H-3-oxa-perfluorododecenyl) -2- {2- [2- (2-Methoxyethoxy) -ethoxy] -ethoxy} -acetamide 7.69 g (37.29 mmol) of dicyclohexylcarbodiimide was added to 20 g (29.83 mmol) of the title compound of Example 10c and {2- [2- (2-methoxyethoxy)]. -Ethoxy] -ethoxy] -acetic acid (voegtle et al., Liebigs Ann. Chem., 1980, 858-862) 6.63 mg (29.83 mmol) and N-hydroxysuccinimide 3.43 mg (29.83 mmol) dimethylformamide Add to solution in 200 ml at 0 ° C. and bring it to 0 ° C. For 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, 20.1 g of viscous oil (theoretical 77%)
Elemental analysis:

e) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H-3-oxa-perfluorododecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy ] -Ethoxy} -acetamide, methanesulfonate 2.09 g (21.72 mmol) of methanesulfonic acid and 3.0 g of palladium catalyst (10% Pd / C) 19.0 g (21.72 mmol) of the title compound of Example 10d Of ethanol in 300 ml of ethanol and hydrogenate it at room temperature for 24 hours. The catalyst is filtered and the filtrate is evaporated to dryness under vacuum.
Yield: 18.2 g of colorless solid (quantitative)
Elemental analysis:

f) N-{[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H, 4H, 4H, -3-oxa-perfluorododecyl) -2- {2- [2- (2-methoxy Ethoxy) -ethoxy] -ethoxy} -acetamide, Gd complex 15.8 g (18.9 mmol) of the title compound of Example 10e, 2.18 g (18.9 mmol) of N-hydroxysuccinimide, 1.60 g (37.80 mmol) of lithium chloride. ) And 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7, Gd complex (WO98 / 24775, Schering AG, (Example 1)) which is 11.90 g (18.30 mmol) of 10-tetraazacyclododecane is dissolved in 200 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 4.87 g (23.63 mmol) of dicyclohexylcarbodiimide and 1.91 g (18.9 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 16.7 g of colorless solid (theoretical value 61%)
Moisture content (Karl Fischer method): 6.9%
Elemental analysis (anhydrous relative ratio):

ｂ）１−Ｎ−（ベンジルオキシカルボニル）−１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ，７Ｈ，７Ｈ，８Ｈ，８Ｈ，−３−アザ−６−オキソ−ペルフルオロヘキサデシルアミン
ＴＨＦ１５０ｍｌ中実施例１１ａの表題化合物４８．０ｇ（６８．７３ｍｍｏｌ）を（ＴＨＦ中）１０Ｍボランジメチルスルフィド５０ｍｌと混合し、５時間還流する。それを０℃に冷却し、メタノール１００ｍｌを滴下にて添加し、それを室温にて１時間撹拌後、真空下において、乾燥状態に蒸発させる。残留物をエタノール３００ｍｌ／１Ｍ塩酸５０ｍｌからなる混合物に取り出し、それを４０℃にて１４時間撹拌する。真空下において、それを乾燥状態に蒸発させ、残留物を５％水酸化ナトリウム溶液３００ｍｌに取り出し、それをジクロロメタン各３００ｍｌで３回抽出する。混合した有機相を硫酸マグネシウムで乾燥させ、真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール１０：１）。
収率：無色固体３０．２ｇ（理論値６４％）
元素分析：

Example 11
a) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 5H, 5H, 7H, 7H, 8H, 8H, -3-aza-4-oxa-6-oxo-perfluorohexadecylamine chloride 17.8 g (140 mmol) of oxalyl is added to 52.21 g (100 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid (eg EP01 / 08498 39 g) in 500 ml of dichloromethane, Is stirred for 14 hours at room temperature. Under vacuum it was evaporated to dryness, the residue was dissolved in 400 ml dichloromethane and 23.31 g N-benzyloxycarbonyl-ethylenediamine (Atwell et al., Synthesis, 1984, 1032-1033) at 0 ° C. 120 mmol) and 10.2 g (100 mmol) of triethylamine and it is stirred for more than 24 hours at room temperature. The reaction solution is mixed with 400 ml of 1N hydrochloric acid and stirred thoroughly for 15 minutes. The organic phase is separated off, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate / hexane 1: 2).
Yield: 49.6 g of colorless wax (theoretical 71%)
Elemental analysis:

b) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H, 7H, 7H, 8H, 8H, -3-aza-6-oxo-perfluorohexadecylamine 150 ml THF 48.0 g (68.73 mmol) of the title compound of middle example 11a is mixed with 50 ml of 10M borane dimethyl sulfide (in THF) and refluxed for 5 hours. It is cooled to 0 ° C., 100 ml of methanol are added dropwise, it is stirred for 1 hour at room temperature and then evaporated to dryness under vacuum. The residue is taken up in a mixture consisting of 300 ml of ethanol / 50 ml of 1M hydrochloric acid and stirred at 40 ° C. for 14 hours. Under vacuum, it is evaporated to the dry state, the residue is taken up in 300 ml of 5% sodium hydroxide solution and it is extracted three times with 300 ml of dichloromethane each. The combined organic phases are dried over magnesium sulfate, evaporated to dryness under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 10: 1).
Yield: 30.2 g of colorless solid (theoretical value 64%)
Elemental analysis:

ｄ）Ｎ−（２−アミノエチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−オキサ−ペルフルオロトリデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド、メタンスルホン酸塩
メタンスルホン酸２．０６ｇ（２１．３８ｍｍｏｌ）およびパラジウム触媒（１０％Ｐｄ／Ｃ）３．０ｇを実施例１１ｃの表題化合物１９．０ｇ（２１．３８ｍｍｏｌ）のエタノール３００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１８．２ｇ（定量）
元素分析：

c) N- [2- (Benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -2- {2- [ 2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetamide 7.42 g (36.59 mmol) of dicyclohexylcarbodiimide was added to 20 g (29.22 mmol) of the title compound of Example 11b and {2- [2- (2-methoxy Ethoxy) -ethoxy] -ethoxy} -acetic acid (voegtle et al., Liebigs Ann. Chem., 1980, 858-862) 6.49 g (29.22 mmol) and 3.29 mg (29.22 mmol) of N-hydroxysuccinimide Add to a solution in 200 ml of dimethylformamide at 0 ° C. This is stirred at 0 ° C. for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, viscous oil 20.3 g (theoretical 78%)
Elemental analysis:

d) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -2- {2- [2- (2- Methoxyethoxy) -ethoxy] -ethoxy} -acetamide, methanesulfonate 2.06 g (21.38 mmol) of methanesulfonic acid and 3.0 g of palladium catalyst (10% Pd / C) 19.0 g of the title compound of Example 11c Add (21.38 mmol) of solution in 300 ml of ethanol and hydrogenate it at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 18.2 g of colorless solid (quantitative)
Elemental analysis:

e) N-{[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -2- {2- [2- (2-Methoxyethoxy) -ethoxy] -ethoxy} -acetamide, Gd complex 15.8 g (18.55 mmol) of the title compound of Example 11d, 2.14 g (18.55 mmol) of N-hydroxysuccinimide, 1.57 g of lithium chloride (37.10 mmol) and 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl The Gd complex (WO98 / 24775, Schering AG, (Example 1)) which is 11.68 g (18.55 mmol) of 1,4,7,10-tetraazacyclododecane in 200 ml of dimethyl sulfoxide with slight heating Dissolve in At 10 ° C., 4.78 g (23.19 mmol) of dicyclohexylcarbodiimide and 1.88 g (18.55 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir it for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 19.8 g of colorless solid (theoretical 73%)
Moisture content (Karl Fischer method): 6.5%
Elemental analysis (anhydrous relative ratio):

ｂ）Ｎ−（２−アミノエチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−（２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−エトキシ）−アセトアミド、メタンスルホン酸塩
メタンスルホン酸２．２８ｇ（２３．６３ｍｍｏｌ）およびパラジウム触媒（１０％Ｐｄ／Ｃ）４．０ｇを実施例１２ａの表題化合物２１ｇ（２３．６３ｍｍｏｌ）のエタノール５００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体２０．１ｇ（定量）
元素分析：

ｃ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−アミノエチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−（２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−エトキシ）−アセトアミド、Ｇｄ錯体
実施例１２ｂの表題化合物１６．９ｇ（１９．８８ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド２．２９ｇ（１９．８８ｍｍｏｌ）、塩化リチウム１．６８ｇ（３９．７６ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン１２．５２ｇ（１９．８８ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド２００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド５．１３ｇ（２４．８５ｍｍｏｌ）およびトリエチルアミン２．０１ｇ（１９．８８ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１８．１ｇ（理論値６２％）
水分量（カール・フィッシャー法）：６．８％
元素分析（無水物質相対比）：

Example 12
a) N- [2- (benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (2- {2- [2- (2-methoxyethoxy) -ethoxy ] -Ethoxy} -ethoxy) -acetamide Dicyclohexylcarbodiimide 8.05 g (39.04 mmol) was replaced with 20 g (31.23 mmol) of the title compound of Example 1a and (2- {2- [2- (2-methoxyethoxy) -ethoxy ] -Ethoxy} -ethoxy) -acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) 8.32 g (31.23 mmol) and N-hydroxysuccinimide 3.59 mg (31.23 mmol) dimethyl Add to solution in 200 ml formamide at 0 ° C. Stir at 3 ° C. for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, 22.1 g of viscous oil (theoretical value 80%)
Elemental analysis:

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy}- Ethoxy) -acetamide, methanesulfonate 2.28 g (23.63 mmol) of methanesulfonic acid and 4.0 g of palladium catalyst (10% Pd / C) in 500 ml of ethanol of 21 g (23.63 mmol) of the title compound of Example 12a Add to solution and hydrogenate it at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 20.1 g of colorless solid (quantitative)
Elemental analysis:

c) N-{[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (2- {2- [2- (2-methoxyethoxy) -ethoxy]- Ethoxy} -ethoxy) -acetamide, Gd Complex 16.9 g (19.88 mmol) of the title compound of Example 12b, 2.29 g (19.88 mmol) of N-hydroxysuccinimide, 1.68 g (39.76 mmol) of lithium chloride and 1 , 4,7-Tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10- Gd complex (WO98 / 24775, Schering AG, (Example 1)) which is 12.52 g (19.88 mmol) of tetraazacyclododecane is dissolved in 200 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 5.13 g (24.85 mmol) of dicyclohexylcarbodiimide and 2.01 g (19.88 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 18.1 g of colorless solid (theoretical 62%)
Moisture content (Karl Fischer method): 6.8%
Elemental analysis (anhydrous relative ratio):

ｂ）Ｎ−（２−アミノエチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−メトキシアセトアミド、メタンスルホン酸塩
メタンスルホン酸２．２３ｇ（２３．１６ｍｍｏｌ）およびパラジウム触媒（１０％Ｐｄ／Ｃ）４．０ｇを実施例１３ａの表題化合物１６．５ｇ（２３．１６ｍｍｏｌ）のエタノール５００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１５．１ｇ（定量）
元素分析：

ｃ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−アミノエチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−メトキシアセトアミド、Ｇｄ錯体
実施例１３ｂの表題化合物１１．７ｇ（１７．２９ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド１．９９ｇ（１７．２９ｍｍｏｌ）、塩化リチウム１．４６ｇ（３４．５８ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン１０．８９ｇ（１７．２９ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド２００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド４．４６ｇ（２１．６ｍｍｏｌ）およびトリエチルアミン１．７５ｇ（１７．２９ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、それを１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１２．９ｇ（理論値５９％）
水分量（カール・フィッシャー法）：６．０％
元素分析（無水物質相対比）：

Example 13
a) N- [2- (Benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2-methoxyacetamide 8.05 g (39.04 mmol) of dicyclohexylcarbodiimide of Example 1a To a solution of 20 g (31.23 mmol) of the title compound and 2.81 g (31.23 mmol) of 2-methoxyacetic acid (Aldrich) and 3.59 g (31.23 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide at 0 ° C. It is stirred for 3 hours at 0 ° C. and then for 16 hours at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, 17.1 g of viscous oil (theoretical value 77%)
Elemental analysis:

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2-methoxyacetamide, methanesulfonate 2.23 g (23.16 mmol) methanesulfonic acid and palladium catalyst ( 4.0 g of 10% Pd / C) is added to a solution of 16.5 g (23.16 mmol) of the title compound of example 13a in 500 ml of ethanol and it is hydrogenated at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 15.1 g of colorless solid (quantitative)
Elemental analysis:

c) N-{[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2-methoxyacetamide, Gd complex 11.7 g (17.29 mmol) of the title compound of Example 13b N-hydroxysuccinimide 1.99 g (17.29 mmol), 1.46 g (34.58 mmol) lithium chloride and 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza- Gd complex which is 10.89 g (17.29 mmol) of 4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane (WO 98/24775, Schering AG, (Example 1)) is dissolved in 200 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 4.46 g (21.6 mmol) of dicyclohexylcarbodiimide and 1.75 g (17.29 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir it for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 12.9 g of colorless solid (theoretical value: 59%)
Moisture content (Karl Fischer method): 6.0%
Elemental analysis (anhydrous relative ratio):

Example 14
a) N- [2- (benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy } -Acetamide Dicyclohexylcarbodiimide (8.05 g, 39.04 mmol) was added to 20 g (31.23 mmol) of the title compound of Example 1a and {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetic acid (Vogetle et al. al., Liebigs Ann. Chem., 1980, 858-862) 6.94 g (31.23 mmol) and N-hydroxysuccinimide 3.59 mg (31.23 mmol) in 200 ml dimethylformamide at 0 ° C. It is 3 hours at 0 ° C. and then 16 hours at room temperature. Stir for hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, viscous oil 22.3 g (theoretical value 85%)
Elemental analysis:

ｃ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−アミノエチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド、Ｇｄ錯体
実施例１４ｂの表題化合物１１．４ｇ（１４．０８ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド１．６２ｇ（１４．０８ｍｍｏｌ）、塩化リチウム１．１９ｇ（２８．１２ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン８．８７ｇ（１４．０８ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド２００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド３．６３ｇ（１７．６ｍｍｏｌ）およびトリエチルアミン１．４３ｇ（１４．０８ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１３．９ｇ（理論値７１％）
水分量（カール・フィッシャー法）：５．７％
元素分析（無水物質相対比）：

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetamide, methane Sulfonate 2.40 g (24.86 mmol) of methanesulfonic acid and 4.0 g of palladium catalyst (10% Pd / C) were added to a solution of 21 g (24.86 mmol) of the title compound of Example 14a in 500 ml of ethanol. Is hydrogenated at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 20.1 g of colorless solid (quantitative)
Elemental analysis:

c) N-{[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy}- Acetamide, Gd complex 11.4 g (14.08 mmol) of the title compound of Example 14b, 1.62 g (14.08 mmol) of N-hydroxysuccinimide, 1.19 g (28.12 mmol) of lithium chloride and 1,4,7-tris -(Carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclod Gd complex (WO 98/24775, Schering AG, (Example 1)), which is 8.87 g (14.08 mmol) of decane, is dissolved in 200 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 3.63 g (17.6 mmol) of dicyclohexylcarbodiimide and 1.43 g (14.08 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 13.9 g of colorless solid (theoretical value 71%)
Moisture content (Karl Fischer method): 5.7%
Elemental analysis (anhydrous relative ratio):

ｂ）Ｎ−（２−アミノエチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−（２−メトキシエトキシ）−アセトアミド、メタンスルホン酸塩
メタンスルホン酸２．１７ｇ（２２．４７ｍｍｏｌ）およびパラジウム触媒（１０％Ｐｄ／Ｃ）３．０ｇを実施例１５ａの表題化合物１７ｇ（２２．４７ｍｍｏｌ）のエタノール５００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１６．２ｇ（定量）
元素分析：

ｃ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−アミノエチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−（２−メトキシエトキシ）−アセトアミド、Ｇｄ錯体
実施例１５ｂの表題化合物１１．５ｇ（１６．０７ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド１．８５ｇ（１６．０７ｍｍｏｌ）、塩化リチウム１．３６ｇ（３２．１４ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン１０．１２ｇ（１６．０７ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド２００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド４．１４ｇ（２０．０８ｍｍｏｌ）およびトリエチルアミン１．６３ｇ（１６．０７ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１４．２ｇ（理論値６７％）
水分量（カール・フィッシャー法）：６．０％
元素分析（無水物質相対比）：

Example 15
a) N- [2- (Benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (2-methoxyethoxy) -acetamide 8.05 g (39.04 mmol) dicyclohexylcarbodiimide ) Of 20 g (31.23 mmol) of the title compound of Example 1a and 4.19 g (31.23 mmol) of (2-methoxyethoxy) -acetic acid (Aldrich) and 3.59 mg (31.23 mmol) of N-hydroxysuccinimide Add to the solution in 200 ml at 0 ° C. and stir it at 0 ° C. for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, 17.5 g of viscous oil (theoretical 74%)
Elemental analysis:

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (2-methoxyethoxy) -acetamide, methanesulfonate 2.17 g of methanesulfonic acid (22. 47 mmol) and 3.0 g of palladium catalyst (10% Pd / C) are added to a solution of 17 g (22.47 mmol) of the title compound of Example 15a in 500 ml of ethanol, which is hydrogenated at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 16.2 g (quantitative) of colorless solid
Elemental analysis:

c) N-{[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (2-methoxyethoxy) -acetamide, Gd complex Title compound of Example 15b 11. 5 g (16.07 mmol), 1.85 g (16.07 mmol) of N-hydroxysuccinimide, 1.36 g (32.14 mmol) of lithium chloride and 1,4,7-tris- (carboxylatomethyl) -10- [1- Carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane 10.12 g (16.07 mmo) l) Gd complex (WO 98/24775, Schering AG, (Example 1)) is dissolved in 200 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 4.14 g (20.08 mmol) of dicyclohexylcarbodiimide and 1.63 g (16.07 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 14.2 g of colorless solid (theoretical 67%)
Moisture content (Karl Fischer method): 6.0%
Elemental analysis (anhydrous relative ratio):

ｂ）Ｎ−［３−（ベンジルオキシカルボニル）−アミノプロピル−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド
ジシクロヘキシルカルボジイミド７．９９ｇ（３８．７４ｍｍｏｌ）を実施例１６ａの表題化合物２０ｇ（３０．９９ｍｍｏｌ）および｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−酢酸（Ｖｏｅｇｔｌｅ ｅｔ ａｌ．，Ｌｉｅｂｉｇｓ Ａｎｎ．Ｃｈｅｍ．，１９８０，８５８−８６２）６．８９ｇ（３０．９９ｍｍｏｌ）ならびにＮ−ヒドロキシスクシンイミド３．５６ｇ（３０．９９ｍｍｏｌ）のジメチルホルムアミド２００ｍｌ中溶液に０℃にて添加し、それを０℃にて３時間および次いで室温にて１６時間撹拌する。析出した尿素を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール２０：１）。
収率：無色、粘性油２１．５ｇ（理論値８１％）
元素分析：

ｃ）Ｎ−（３−アミノプロピル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド、メタンスルホン酸塩
メタンスルホン酸２．２５ｇ（２３．２９ｍｍｏｌ）およびパラジウム触媒（１０％Ｐｄ／Ｃ）４．０ｇを実施例１６ｂの表題化合物２０ｇ（２３．２９ｍｍｏｌ）のエタノール５００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１９．２ｇ（定量）
元素分析：

ｄ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−３−アミノプロピル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド、Ｇｄ錯体
実施例１６ｃの表題化合物１１．３ｇ（１３．８０ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド１．５９ｇ（１３．８０ｍｍｏｌ）、塩化リチウム１．１７ｇ（２７．６０ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン８．７９ｇ（１３．８０ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド２００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド３．５９ｇ（１７．４ｍｍｏｌ）およびトリエチルアミン１．４０ｇ（１３．８０ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１２．９ｇ（理論値６６％）
水分量（カール・フィッシャー法）：６．０％
元素分析（無水物質相対比）：

Example 16
a) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 3H, 3H, 4H, 4H, 6H, 6H, -4-aza-perfluorotetradecylamine N-benzyloxycarbonyl-propylenediamine ( Atwell et al., Synthesis, 1984, 1032-1033) 25.0 g (120 mmol) and 10.2 g (100 mmol) of triethylamine in 500 ml acetonitrile methanesulfonic acid- (1H, 1H, 2H, 2H-perfluorodecyl) -ester ( Bartsch et al., Tetrahedron, 2000, 3291-3302) is added to 54.22 g (100 mmol) and stirred at 60 ° C. for 48 hours. Insoluble constituents are filtered off from the reaction solution, it is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: 40.7 g of colorless wax (theoretical value 62%)
Elemental analysis:

b) N- [3- (benzyloxycarbonyl) -aminopropyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy } -Acetamide 7.99 g (38.74 mmol) of dicyclohexylcarbodiimide was added to 20 g (30.99 mmol) of the title compound of Example 16a and {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) 6.89 g (30.99 mmol) and 3.56 g (30.99 mmol) N-hydroxysuccinimide in 200 ml dimethylformamide at 0 ° C. It is 3 hours at 0 ° C. and then 1 at room temperature. Stir for 6 hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, 21.5 g of viscous oil (theoretical value 81%)
Elemental analysis:

c) N- (3-aminopropyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetamide, methane Sulfonate 2.25 g (23.29 mmol) methanesulfonic acid and 4.0 g palladium catalyst (10% Pd / C) were added to a solution of 20 g (23.29 mmol) of the title compound of Example 16b in 500 ml ethanol. Is hydrogenated at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 19.2 g of colorless solid (quantitative)
Elemental analysis:

d) N-{[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-3-aminopropyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy}- Acetamide, Gd complex 11.3 g (13.80 mmol) of the title compound of Example 16c, 1.59 g (13.80 mmol) of N-hydroxysuccinimide, 1.17 g (27.60 mmol) of lithium chloride and 1,4,7-tris -(Carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclo A Gd complex (WO 98/24775, Schering AG, (Example 1)) which is 8.79 g (13.80 mmol) of dodecane is dissolved in 200 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 3.59 g (17.4 mmol) of dicyclohexylcarbodiimide and 1.40 g (13.80 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 12.9 g of colorless solid (theoretical 66%)
Moisture content (Karl Fischer method): 6.0%
Elemental analysis (anhydrous relative ratio):

ｂ）Ｎ−［４−（ベンジルオキシカルボニル）−アミノブチル−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド
ジシクロヘキシルカルボジイミド７．７１ｇ（３７．４ｍｍｏｌ）を実施例１７ａの表題化合物２０ｇ（２９．９２ｍｍｏｌ）および｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−酢酸（Ｖｏｅｇｔｌｅ ｅｔ ａｌ．，Ｌｉｅｂｉｇｓ Ａｎｎ．Ｃｈｅｍ．，１９８０，８５８−８６２）６．６５ｇ（２９．９２ｍｍｏｌ）ならびにＮ−ヒドロキシスクシンイミド３．４４ｇ（２９．９２ｍｍｏｌ）のジメチルホルムアミド２００ｍｌ中溶液に０℃にて添加し、それを０℃にて３時間および次いで室温にて１６時間撹拌する。析出した尿素を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール２０：１）。
収率：無色、粘性油２６．０ｇ（理論値７９％）
元素分析：

ｃ）Ｎ−（４−アミノブチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド パラジウム触媒（１０％Ｐｄ／Ｃ）４．０ｇを実施例１７ｂの表題化合物２０ｇ（２２．９２ｍｍｏｌ）のエタノール５００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１７．０ｇ（定量）
元素分析：

ｄ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−４−アミノブチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド、Ｇｄ錯体
実施例１７ｃの表題化合物１０ｇ（１３．５４ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド１．５６ｇ（１３．５４ｍｍｏｌ）、塩化リチウム１．１４ｇ（２６．０８ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン８．６９ｇ（１３．５４ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド２００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド３．５３ｇ（１７．０７ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１１．７ｇ（理論値６０％）
水分量（カール・フィッシャー法）：６．５％
元素分析（無水物質相対比）：

Example 17
a) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 3H, 3H, 4H, 4H, 6H, 6H, 7H, 7H-5-aza-perfluoropentadecylamine N-benzyloxycarbonyl- 26.67 g (120 mmol) of butylenediamine (Atwell et al., Synthesis, 1984, 1032-1033) and 10.2 g (100 mmol) of triethylamine in 500 ml of acetonitrile-methanesulfonic acid- (1H, 1H, 2H, 2H-perfluorodecyl) ) -Ester (Bartsch et al., Tetrahedron, 2000, 3291-3302) is added to 54.22 g (100 mmol) and it is stirred at 60 ° C. for 48 hours. Insoluble constituents are filtered off from the reaction solution, it is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: 39.6 g of colorless wax (theoretical value: 59%)
Elemental analysis:

b) N- [4- (benzyloxycarbonyl) -aminobutyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy } -Acetamide 7.71 g (37.4 mmol) of dicyclohexylcarbodiimide was added to 20 g (29.92 mmol) of the title compound of Example 17a and {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) 6.65 g (29.92 mmol) and N-hydroxysuccinimide 3.44 g (29.92 mmol) in 200 ml dimethylformamide at 0 ° C. It is 3 hours at 0 ° C. and then 16 hours at room temperature Stir for a while. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, 26.0 g of viscous oil (theoretical value 79%)
Elemental analysis:

c) N- (4-aminobutyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetamide palladium catalyst 4.0 g of (10% Pd / C) is added to a solution of 20 g (22.92 mmol) of the title compound of example 17b in 500 ml of ethanol and it is hydrogenated at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 17.0 g of colorless solid (quantitative)
Elemental analysis:

d) N-{[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-4-aminobutyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy}- Acetamide, Gd complex 10 g (13.54 mmol) of the title compound of Example 17c, 1.56 g (13.54 mmol) of N-hydroxysuccinimide, 1.14 g (26.08 mmol) of lithium chloride and 1,4,7-tris- ( Carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododeca 8.69 g (13.54 mmol) of the Gd complex (WO 98/24775, Schering AG, (Example 1)) is dissolved in 200 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 3.53 g (17.07 mmol) of dicyclohexylcarbodiimide is added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 11.7 g of colorless solid (theoretical value: 60%)
Moisture content (Karl Fischer method): 6.5%
Elemental analysis (anhydrous relative ratio):

ｂ）Ｎ−（２−アミノエチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ−３−オキサ−ペルフルオロデシル）−２−［２−（２−メトキシエトキシ）−エトキシ］−アセトアミド、メタンスルホン酸塩
メタンスルホン酸１．９８ｇ（２０．５０ｍｍｏｌ）およびパラジウム触媒（１０％Ｐｄ／Ｃ）３．０ｇを実施例１８ｃの表題化合物１７．０ｇ（２０．５０ｍｍｏｌ）のエタノール３００ｍｌ中溶液に添加し、それを室温にて２４時間水素化する。触媒を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させる。
収率：無色固体１６．３ｇ（定量）
元素分析：

ｃ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−アミノエチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ−３−オキサ−ペルフルオロデシル）−２−［２−（２−メトキシエトキシ）−エトキシ］−アセトアミド、Ｇｄ錯体
実施例１８ｄの表題化合物１４．７５ｇ（１８．３０ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド２．１１ｇ（１８．３０ｍｍｏｌ）、塩化リチウム１．５５ｇ（３６．６０ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン１１．５２ｇ（１８．３０ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド２００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド４．７２ｇ（２２．８８ｍｍｏｌ）およびトリエチルアミン１．８５ｇ（１８．３０ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１７．６ｇ（理論値６９％）
水分量（カール・フィッシャー法）：６．１％
元素分析（無水物質相対比）：

Example 18
a) N- [2- (Benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H, 4H, 4H-3-oxa-perfluorodecyl) -2- [2- (2-methoxyethoxy) -Ethoxy] -acetamide 7.69 g (37.29 mmol) of dicyclohexylcarbodiimide was added to 20 g (29.83 mmol) of the title compound of Example 10c and 5.32 g of [2- (2-methoxyethoxy) -ethoxy] -acetic acid (Aldrich). 29.83 mmol) and 3.43 mg (29.83 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide at 0 ° C., and it is stirred at 0 ° C. for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, 17.9 g viscous oil (theoretical 72%)
Elemental analysis:

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H-3-oxa-perfluorodecyl) -2- [2- (2-methoxyethoxy) -ethoxy] -acetamide Methanesulfonate 1.98 g (20.50 mmol) of methanesulfonic acid and 3.0 g of palladium catalyst (10% Pd / C) in a solution of 17.0 g (20.50 mmol) of the title compound of Example 18c in 300 ml of ethanol. Add and hydrogenate it at room temperature for 24 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under vacuum.
Yield: 16.3 g of colorless solid (quantitative)
Elemental analysis:

c) N-{[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H, 4H, 4H-3-oxa-perfluorodecyl) -2- [2- (2-methoxyethoxy) -ethoxy ] -Acetamide, Gd complex 14.75 g (18.30 mmol) of the title compound of Example 18d, 2.11 g (18.30 mmol) of N-hydroxysuccinimide, 1.55 g (36.60 mmol) of lithium chloride and 1,4,7 -Tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraaza Gd complex (WO 98/24775, Schering AG, (Example 1)), which is 11.52 g (18.30 mmol) of cyclododecane, is dissolved in 200 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 4.72 g (22.88 mmol) of dicyclohexylcarbodiimide and 1.85 g (18.30 mmol) of triethylamine are added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 17.6 g of colorless solid (theoretical value: 69%)
Water content (Karl Fischer method): 6.1%
Elemental analysis (anhydrous relative ratio):

ｂ）Ｎ−［５−（ｔｅｒｔ−ブチルオキシカルボニル）−アミノ−３−オキサペンチル−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド
ジシクロヘキシルカルボジイミド３．９７ｇ（１９．２３ｍｍｏｌ）を実施例１９ａの表題化合物１０ｇ（１５．３８ｍｍｏｌ）および｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−酢酸（Ｖｏｅｇｔｌｅ ｅｔ ａｌ．，Ｌｉｅｂｉｇｓ Ａｎｎ．Ｃｈｅｍ．，１９８０，８５８−８６２）３．４２ｇ（１５．３８ｍｍｏｌ）ならびにＮ−ヒドロキシスクシンイミド１．７７ｇ（１５．３８ｍｍｏｌ）のジメチルホルムアミド２００ｍｌ中溶液に０℃にて添加し、それを０℃にて３時間および次いで室温にて１６時間撹拌する。析出した尿素を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール２０：１）。
収率：無色、粘性油９．９ｇ（理論値７５％）
元素分析：

ｃ）Ｎ−（５−アミノ−３−オキサペンチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド
トリフルオロ酢酸５０ｍｌを実施例１９ｂの表題化合物９．５ｇ（１１．１２ｍｍｏｌ）のジクロロメタン１００ｍｌ中溶液に０℃に添加し、室温にて３時間。それを真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール１０：１）。
収率：無色固体７．８ｇ（理論値９３％）
元素分析：

ｄ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−５−アミノ−３−オキサペンチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド、Ｇｄ錯体
実施例１９ｃの表題化合物７ｇ（９．２８ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド１．０７ｇ（９．２８ｍｍｏｌ）、塩化リチウム７８７ｍｇ（１８．５６ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン５．８４ｇ（９．２８ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド１００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド２．３９ｇ（１１．６ｍｍｏｌ）を添加し、室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体８．８ｇ（理論値６５％）
水分量（カール・フィッシャー法）：６．５％
元素分析（無水物質相対比）：

Example 19
a) 1-N- (tert-butyloxycarbonyl) -1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H, 7H, 7H, 8H, 8H-6-aza-3-oxaperfluorohexadecylamine 6.13 g (30 mmol) of N-tert-butyloxycarbonyl-3-oxa-pentylenediamine (Koenig et al., Eur. J. Org. Chem., 2002, 3004-3014) and 2.55 g (25 mmol) of triethylamine Is added to 13.56 g (25 mmol) of methanesulfonic acid- (1H, 1H, 2H, 2H-perfluorodecyl) -ester (Bartsch et al., Tetrahedron, 2000, 3291-3302) in 150 ml of acetonitrile, which is For 48 hours. Insoluble constituents are filtered off from the reaction solution, it is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: 10.9 g of colorless wax (theoretical value 67%)
Elemental analysis:

b) N- [5- (tert-Butyloxycarbonyl) -amino-3-oxapentyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy ) -Ethoxy] -ethoxy} -acetamide 3.97 g (19.23 mmol) of dicyclohexylcarbodiimide and 10 g (15.38 mmol) of the title compound of Example 19a and {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy. } -Acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) 3.42 g (15.38 mmol) and N-hydroxysuccinimide 1.77 g (15.38 mmol) in a solution of 200 ml dimethylformamide. Add at 0 ° C and leave it at 0 ° C for 3 hours And then stirred at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, 9.9 g viscous oil (theoretical 75%)
Elemental analysis:

c) N- (5-amino-3-oxapentyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} Add 50 ml of acetamide trifluoroacetic acid to a solution of 9.5 g (11.12 mmol) of the title compound of example 19b in 100 ml of dichloromethane at 0 ° C. and 3 hours at room temperature. It is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 10: 1).
Yield: 7.8 g of colorless solid (theoretical 93%)
Elemental analysis:

d) N-{[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-5-amino-3-oxapentyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -Ethoxy} -acetamide, Gd complex 7g (9.28 mmol) of the title compound of Example 19c, 1.07 g (9.28 mmol) of N-hydroxysuccinimide, 787 mg (18.56 mmol) of lithium chloride and 1,4,7-tris -(Carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacycl A Gd complex (WO 98/24775, Schering AG, (Example 1)) which is 5.84 g (9.28 mmol) of rhododecane is dissolved in 100 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 2.39 g (11.6 mmol) of dicyclohexylcarbodiimide is added and stirred at room temperature for 16 hours. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 8.8 g of colorless solid (theoretical value: 65%)
Moisture content (Karl Fischer method): 6.5%
Elemental analysis (anhydrous relative ratio):

ｂ）Ｎ−｛４−（ｔｅｒｔ−ブチルオキシカルボニル）−アミノ−［２，３−（２，２−ジメチル−［１，３］−ジオキソラニル）］−ブチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド
ジシクロヘキシルカルボジイミド３．６５ｇ（１７．７ｍｍｏｌ）を実施例２０ａの表題化合物１０ｇ（１４．１６ｍｍｏｌ）および｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−酢酸（Ｖｏｅｇｔｌｅ ｅｔ ａｌ．，Ｌｉｅｂｉｇｓ Ａｎｎ．Ｃｈｅｍ．，１９８０，８５８−８６２）３．１５ｇ（１４．１６ｍｍｏｌ）ならびにＮ−ヒドロキシスクシンイミド１．６３ｇ（１４．１６ｍｍｏｌ）のジメチルホルムアミド２００ｍｌ中溶液に０℃にて添加し、それを０℃にて３時間および次いで室温にて１６時間撹拌する。析出した尿素を濾過して取り除き、濾液を真空下において、乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール２０：１）。
収率：無色、粘性油８．９ｇ（理論値６９％）
元素分析：

ｃ）Ｎ−（４−アミノ−２，３−ジヒドロキシブチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド
トリフルオロ酢酸５０ｍｌを実施例２０ｂの表題化合物８．２ｇ（９．００ｍｍｏｌ）のジクロロメタン１００ｍｌ中溶液に０℃にて添加し、室温にて３時間。真空下において、それを乾燥状態に蒸発させ、残留物をシリカゲルクロマトグラフィーにかける（移動溶媒：ジクロロメタン／メタノール１０：１〜２：１）。
収率：無色固体６．６８ｇ（理論値９６％）
元素分析：

ｄ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−（４−アミノ−２，３−ジヒドロキシブチル）−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド、Ｇｄ錯体
実施例２０ｃの表題化合物６ｇ（７．７９ｍｍｏｌ）、Ｎ−ヒドロキシスクシンイミド８９７ｍｇ（７．７９ｍｍｏｌ）、塩化リチウム６６０ｍｇ（１５．５８ｍｍｏｌ）および１，４，７−トリス−（カルボキシラトメチル）−１０−［１−カルボキシ−３−アザ−４−オキソ−５−メチルペンタン−５−イル］−１，４，７，１０−テトラアザシクロドデカン４．９０ｇ（７．７９ｍｍｏｌ）であるＧｄ錯体（ＷＯ９８／２４７７５、Ｓｃｈｅｒｉｎｇ ＡＧ、（実施例１））をわずかに加熱しながらジメチルスルホキシド１００ｍｌ中に溶解する。１０℃にて、ジシクロヘキシルカルボジイミド２．０１ｇ（９．７４ｍｍｏｌ）を添加し、それを室温にて１６時間撹拌する。溶液をアセトン２０００ｍｌに注ぎ、１０分以上撹拌する。析出固体を濾過し、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体６．９ｇ（理論値５９％）
水分量（カール・フィッシャー法）：７．７％
元素分析（無水物質相対比）：

Example 20
a) 1-N- (tert-butyloxycarbonyl) -1H, 1H, 2H, 3H, 4H, 4H, 6H, 6H, 7H, 7H-5-aza- [2,3- (2,2-dimethyl- [1,3] -Dioxolanyl)]-perfluoropentadecylamine N-tert-butyloxycarbonyl- [2,3- (2,2-dimethyl- [1,3] -dioxolanyl)]-butylenediamine [N-tert (5-aminoethyl-2,2-dimethyl-[-] as in the preparation of butyloxycarbonyl-3-oxa-pentylenediamine (Koenig et al., Eur. J. Org. Chem., 2002, 3004-3014) 1,3] -Dioxolan-4-yl) -methylamine (ACROS)] 7.81 g (30 mmol) and triethylamine 5 g (25 mmol) is added to 13.56 g (25 mmol) of methanesulfonic acid- (1H, 1H, 2H, 2H-perfluorodecyl) -ester (Bartsch et al., Tetrahedron, 2000, 3291-3302) in 150 ml of acetonitrile, It is stirred at 60 ° C. for 48 hours. Insoluble constituents are filtered off from the reaction solution, it is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: 12.5 g of colorless wax (theoretical 71%)
Elemental analysis:

b) N- {4- (tert-Butyloxycarbonyl) -amino- [2,3- (2,2-dimethyl- [1,3] -dioxolanyl)]-butyl} -N- (1H, 1H, 2H , 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetamide 3.65 g (17.7 mmol) of dicyclohexylcarbodiimide was added to 10 g (14.14) of the title compound of Example 20a. 16 mmol) and {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetic acid (voegtle et al., Liebigs Ann. Chem., 1980, 858-862) 3.15 g (14.16 mmol) and 1.63 g (14.16 mmol) of dimethylformamide 200 N-hydroxysuccinimide To the solution in ml is added at 0 ° C. and it is stirred at 0 ° C. for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to the dry state under vacuum and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 20: 1).
Yield: colorless, viscous oil 8.9 g (theoretical 69%)
Elemental analysis:

c) N- (4-amino-2,3-dihydroxybutyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy]- 50 ml of ethoxy} -acetamide trifluoroacetic acid was added at 0 ° C. to a solution of 8.2 g (9.00 mmol) of the title compound of Example 20b in 100 ml of dichloromethane at room temperature for 3 hours. Under vacuum it is evaporated to dryness and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol 10: 1 to 2: 1).
Yield: 6.68 g of colorless solid (theoretical value: 96%)
Elemental analysis:

d) N-{[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-(4-amino-2,3-dihydroxybutyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -Ethoxy] -ethoxy} -acetamide, Gd complex 6g (7.79 mmol) of the title compound of Example 20c, 897 mg (7.79 mmol) of N-hydroxysuccinimide, 660 mg (15.58 mmol) of lithium chloride and 1,4,7- Tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-teto A Gd complex (WO 98/24775, Schering AG, (Example 1)) which is 4.90 g (7.79 mmol) of laazacyclododecane is dissolved in 100 ml of dimethyl sulfoxide with slight heating. At 10 ° C., 2.01 g (9.74 mmol) of dicyclohexylcarbodiimide is added and it is stirred for 16 hours at room temperature. Pour the solution into 2000 ml acetone and stir for more than 10 minutes. The precipitated solid is filtered and then purified by chromatography (RP-18; mobile solvent: water / acetonitrile gradient).
Yield: 6.9 g of colorless solid (theoretical value: 59%)
Moisture content (Karl Fischer method): 7.7%
Elemental analysis (anhydrous relative ratio):

Example 21
a) N-{[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (butanoyl-4- (R) -carboxylato-4 -Yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetamide, Gd Complex monomonosodium salt and N-({1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-N- (ethano- [2- (R) -Carboxylatoethyl] -yl)}-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy } -Acetami , Gd complex mono-sodium salt 2.84 g (3.52 mmol) of the title compound of Example 14b, 448 mg (4.4 mmol) of triethylamine, and 2- (R) -2- [4,7,10-tris- (carboxyl) Latomethyl) -1,4,7,10-tetraazacyclododecan-1-yl] pentanedicarboxylic acid monopentafluorophenyl ester 3.51 g (4.4 mmol) Gd complex (WO2005 / 0014154, EPIX PHARMACEUTICALS, INC (Example 9: EP-2104-15-Pfp)) is dissolved in 50 ml of dimethyl sulfoxide, mixed with 356 mg (3.52 mmol) of triethylamine and stirred for 16 hours at room temperature. Stir for an additional 10 minutes. The solid is filtered and then purified by chromatography (RP-18; mobile solvent: gradient consisting of water / acetonitrile) The fractions containing the product are concentrated by evaporation, dissolved in water and 0.1 N hydroxylated. After neutralization with sodium solution, freeze-dry.
Yield: 2.03 g of colorless solid as a 3: 2 regioisomer mixture (theoretical 39%)
Moisture content (Karl Fischer method): 9.2%
Elemental analysis (anhydrous relative ratio):

Example 22
a) N-{[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (butanoyl-4- (R) -carboxylato-4 -Yl)] 2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (1-O-α-d-mannopyranosyl) -acetamide, Gd complex monomonosodium salt and N- ({1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-N- (ethano- [2- (R) -carboxylatoethyl] -yl) } -2-Aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (1-O-α-d-mannopyranosyl) -acetamide, Gd complex monomonosodium salt Title of Example 1c Compound 2.83 g (3.44 mmol), 436 mg (4.3 mmol) of triethylamine, and 2- (R) -2- [4,7,10-tris- (carboxylatomethyl) -1,4,7,10-tetra Azacyclododecan-1-yl] pentanedicarboxylic acid monopentafluorophenyl ester 3.43 g (4.3 mmol) Gd complex (WO2005 / 0014154, EPIX PHARMACEUTICALS, INC., (Example 9: EP-2104-15) Pfp)) is dissolved in 50 ml of dimethyl sulfoxide, mixed with 348 mg (3.44 mmol) of triethylamine and stirred for 16 hours at room temperature, the solution is poured into 1000 ml of acetone and stirred for more than 10 minutes, the precipitated solid is filtered, It is then purified by chromatography (R . -18; mobile solvent: gradient consisting of water / acetonitrile) product were concentrated by evaporation Fractions containing, dissolved in water, neutralized with 0.1N sodium hydroxide solution and freeze-dried.
Yield: 1.64 g of colorless solid as a 3: 2 regioisomer mixture (theoretical 32%)
Moisture content (Karl Fischer method): 8.8%
Elemental analysis (anhydrous relative ratio):

ｂ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−２−アミノエチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド、Ｄｙ錯体
実施例２３ａの表題化合物２．０ｇ（１．４９ｍｍｏｌ）を水５０ｍｌおよび酢酸１ｍｌに溶解し、塩化ジスプロシウム４４１ｍｇ（１．６４ｍｍｏｌ）と混合し、８０℃にて６時間撹拌する。アンモニアと中和し、乾燥状態に蒸発させ、クロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１．７８ｇ（理論値８４％）
水分量（カール・フィッシャー法）：６．２％
元素分析（無水物質相対比）：

Example 23
a) N-{[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy}- Acetamide, trisodium salt 10 g (7.13 mmol) of the title compound of Example 14c are dissolved in a mixture of 100 ml of water and 30 ml of isopropanol, mixed with 2.25 g (24.96 mmol) of oxalic acid and heated to 100 ° C. for 5 hours. To do. After cooling to room temperature, the precipitated solid is then purified by chromatography (RP-18; mobile solvent: gradient consisting of water / acetonitrile). The fraction containing the product is concentrated by evaporation, dissolved in water, fixed at pH 10 with 0.1N sodium hydroxide solution and lyophilized.
Yield: 7.39 g of colorless solid (theoretical 77%)
Moisture content (Karl Fischer method): 8.2%
Elemental analysis (anhydrous relative ratio):

b) N-{[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy}- Acetamide, Dy complex 2.0 g (1.49 mmol) of the title compound of Example 23a is dissolved in 50 ml of water and 1 ml of acetic acid, mixed with 441 mg (1.64 mmol) of dysprosium chloride and stirred at 80 ° C. for 6 hours. Neutralize with ammonia, evaporate to dryness and purify by chromatography (RP-18; mobile solvent: gradient consisting of water / acetonitrile).
Yield: 1.78 g of colorless solid (theoretical 84%)
Water content (Karl Fischer method): 6.2%
Elemental analysis (anhydrous relative ratio):

Example 24
a) N-{[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy}- Acetamide, Yb Complex 2.0 g (1.49 mmol) of the title compound of Example 23a is dissolved in 50 ml of water and 1 ml of acetic acid, mixed with 458 mg (1.64 mmol) of ytterbium chloride, and stirred at 80 ° C. for 6 hours. Neutralize with ammonia, evaporate to dryness and purify by chromatography (RP-18; mobile solvent: gradient consisting of water / acetonitrile).
Yield: 1.84 g of colorless solid (theoretical value: 86%)
Moisture content (Karl Fischer method): 6.9%
Elemental analysis (anhydrous relative ratio):

Example 25
a) N-{[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5- Methyl-5-yl)]-2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy}- Acetamide, Y complex 2.0 g (1.49 mmol) of the title compound of Example 23a is dissolved in 50 ml of water and 1 ml of acetic acid, mixed with 320 mg (1.64 mmol) of yttrium chloride and stirred at 80 ° C. for 6 hours. Neutralize with ammonia, evaporate to dryness and purify by chromatography (RP-18; mobile solvent: gradient consisting of water / acetonitrile).
Yield: 1.56 g of colorless solid (theoretical value: 79%)
Moisture content (Karl Fischer method): 5.5%
Elemental analysis (anhydrous relative ratio):

ｂ）１０−（５−オキソ−テトラヒドロフラン−２−イルメチル）−１，４，７−トリス（カルボキシメチル）−１，４，７，１０−テトラアザシクロドデカン、Ｇｄ錯体
実施例２６ａの表題化合物１２．０ｇ（２４．２ｍｍｏｌ）を水１００ｍｌおよび酢酸１ｍｌに溶解し、酸化ガドリニウム４．３９ｇ（１２．１ｍｍｏｌ）と混合し、８０℃にて６時間撹拌する。溶液を濾過し、乾燥状態に蒸発させ、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１３．８ｇ（理論値８９％）
水分量（カール・フィッシャー法）：６．５％
元素分析（無水物質相対比）：

ｃ）Ｎ−｛［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−４−ヒドロキシ−５−イル）］−２−アミノエチル｝−Ｎ−（１Ｈ，１Ｈ，２Ｈ，２Ｈ−ペルフルオロデシル）−２−｛２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド、Ｇｄ錯体
実施例１４ｂの表題化合物２．８４ｇ（３．５２ｍｍｏｌ）および実施例２６ｂの表題化合物３．３８ｇ（５．２８ｍｍｏｌ）をメタノール５０ｍｌに溶解し、トリエチルアミン３５６ｍｇ（３．５２ｍｍｏｌ）と混合し、５０℃にて４８時間撹拌する。それを乾燥状態に蒸発させ、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体３．２７ｇ（理論値６６％）
水分量（カール・フィッシャー法）：６．９％
元素分析（無水物質相対比）：

Example 26
a) 10- (5-Oxo-tetrahydrofuran-2-ylmethyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane Sodium hydroxide 8.3 g (207.6 mmol) Is added to 12.0 g (34.6 mmol) of 1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane (D03A) in 50 ml of water. A solution consisting of 5.02 g (43.25 mmol) of 3-oxiranylpropionic acid (Dakoji et al., J. Am. Chem. Soc., 1996, 10971-1079) in 50 ml of n-butanol / 2 ml of propanol. There it is added dropwise and the solution is heated to 80 ° C. for 24 hours. The reaction solution is evaporated to dryness under vacuum, the residue is mixed with 300 ml of water and fixed at pH 3 with 3N hydrochloric acid. It is then extracted 3 times with 200 ml each of n-butanol, the combined butanol phases are evaporated to dryness under vacuum and the residue is purified by chromatography (RP-18; mobile solvent: from water / acetonitrile). The gradient).
Yield: 13.6 g of colorless solid (theoretical value: 79%)
Moisture content (Karl Fischer method): 10.4%
Elemental analysis (anhydrous relative ratio):

b) 10- (5-Oxo-tetrahydrofuran-2-ylmethyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane, Gd complex Title compound 12 of Example 26a 0.0 g (24.2 mmol) is dissolved in 100 ml water and 1 ml acetic acid, mixed with 4.39 g (12.1 mmol) gadolinium oxide and stirred at 80 ° C. for 6 hours. The solution is filtered, evaporated to dryness and then purified by chromatography (RP-18; mobile solvent: gradient consisting of water / acetonitrile).
Yield: 13.8 g of colorless solid (theoretical 89%)
Moisture content (Karl Fischer method): 6.5%
Elemental analysis (anhydrous relative ratio):

c) N-{[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-10-N- (pentanoyl-4-hydroxy-5-yl)]- 2-Aminoethyl} -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetamide, Gd complex of Example 14b 2.84 g (3.52 mmol) of the title compound and 3.38 g (5.28 mmol) of the title compound of Example 26b were dissolved in 50 ml of methanol, mixed with 356 mg (3.52 mmol) of triethylamine, and stirred at 50 ° C. for 48 hours. To do. It is evaporated to dryness and then purified by chromatography (RP-18; mobile solvent: gradient consisting of water / acetonitrile).
Yield: 3.27 g of colorless solid (theoretical 66%)
Moisture content (Karl Fischer method): 6.9%
Elemental analysis (anhydrous relative ratio):

Example 27
a) 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane- 10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-perfluorotridecyl-N-{-2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -Acetamide, Gd complex 2.58 g (12.5 mmol) of dicyclohexylcarbodiimide and 1.01 g (10 mmol) of triethylamine, 12.14 g (10 mmol) of the title compound of Example 2b and {2- [2- (2-methoxyethoxy)- Ethoxy] -ethoxy] -acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) 2. 22 g (10 mmol) and 1.15 mg (10 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0 ° C. and it is stirred at 0 ° C. for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off and the filtrate is evaporated to dryness under vacuum. The residue is taken up in a little water, insoluble constituents are filtered off and the filtrate is then purified by chromatography (RP-18; mobile solvent: gradient consisting of water / acetonitrile).
Yield: 8.2 g of colorless solid (theoretical value: 58%)
Water content (Karl Fischer method): 6.2%
Elemental analysis (anhydrous relative ratio):

ｂ）１Ｈ，１Ｈ，２Ｈ，２Ｈ，４Ｈ，４Ｈ，５Ｈ，５Ｈ−３−Ｎ−［１，４，７−トリス−（カルボキシラトメチル）−１，４，７，１０−テトラアザシクロドデカン−１０−Ｎ−（ペンタノイル−３−アザ−４−オキソ−５−メチル−５−イル）］−ペルフルオロトリデシル−Ｎ−｛−２−［２−（２−メトキシエトキシ）−エトキシ］−エトキシ｝−アセトアミド、Ｙ錯体
実施例２８ａの表題化合物２．０ｇ（１．５０ｍｍｏｌ）を水５０ｍｌおよび酢酸１ｍｌに溶解し、塩化イットリウム３２０ｍｇ（１．６４ｍｍｏｌ）と混合し、８０℃にて６時間撹拌する。アンモニアと中和し、乾燥状態に蒸発させ、次いでクロマトグラフィーにより精製する（ＲＰ−１８；移動溶媒：水／アセトニトリルからなる勾配）。
収率：無色固体１．４３ｇ（理論値７２％）
水分量（カール・フィッシャー法）：５．０％
元素分析（無水物質相対比）：

Example 28
a) 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane- 10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-perfluorotridecyl-N-{-2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -Acetamide, trisodium salt 10 g (7.11 mmol) of the title compound of example 27a are dissolved in a mixture of 100 ml of water and 30 ml of isopropanol, mixed with 2.25 g (24.96 mmol) of oxalic acid and at 100 ° C. for 5 hours. Heat. After cooling to room temperature, the precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient consisting of water / acetonitrile). The fraction containing the product is concentrated by evaporation, dissolved in water, fixed at pH 8 with 0.1N sodium hydroxide solution and lyophilized.
Yield: 8.64 g of colorless solid (theoretical value: 91%)
Moisture content (Karl Fischer method): 7.5%
Elemental analysis (anhydrous relative ratio):

b) 1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane- 10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-perfluorotridecyl-N-{-2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -Acetamide, Y complex 2.0 g (1.50 mmol) of the title compound of Example 28a is dissolved in 50 ml of water and 1 ml of acetic acid, mixed with 320 mg (1.64 mmol) of yttrium chloride and stirred at 80 ° C. for 6 hours. Neutralize with ammonia, evaporate to dryness and then purify by chromatography (RP-18; mobile solvent: gradient consisting of water / acetonitrile).
Yield: 1.43 g of colorless solid (theoretical 72%)
Moisture content (Karl Fischer method): 5.0%
Elemental analysis (anhydrous relative ratio):

Example 29: Relaxation capacity The concentration of gadolinium complex, the title substance of Examples 1d, 5c, 14c, 15c, contained in water and plasma (bovine) was increased, and these relaxation times T1 and T2 were measured with an NMR + spectrometer ( Measurements were made at 0.47 T, 40 ° C. using a Minispec PC20). The results are shown in Table 1 below.

Example 30: Acute toxicity after single intravenous administration in mice (preliminary study)
After intravenous administration of the gadolinium complex, the title substance of Examples 1d, 5c, 14c, 15c, to mice (n = 3; injection rate: 2 ml / min), acute systemic suitability (LD ₅₀ ) was preliminarily It was measured. In each case, several doses were examined with a 7-day observation period. The expected acute toxicity can be shown in Table 1.

Example 31: Excretion after Intravenous Administration in Rats After the intravenous administration of the title substances gadolinium complex of Examples 1d, 5c, 14c, 15c, total gadolinium amount 50 μmol / kg body weight to rats (n = 3), Using atomic emission spectroscopy (ICP-AES), the amount of metal was measured in the excretory medium material of manure and the fraction of the body (residual amount) up to 14 days after administration. The results are shown in Table 1.

Example 32: Plasma Dynamics after Intravenous Administration in Rats After intravenous administration to rats (n = 3) of gadolinium complexes as the title substances of Examples 1d, 5c, 14c and 15c, total gadolinium amount 50 μmol / kg body weight Blood samples were taken at each time point (8-24 hours pi) through the common carotid artery catheter and the metal content was measured using atomic emission spectroscopy (ICP-AES). The plasma value was converted via a conversion factor (0.625). The elimination half-life was calculated from the plasma concentration using specific software (WinNonlin). The results are shown in Table 1.

Example 33: Visualization of lymph node metastasis and primary tumor after intravenous administration of contrast agent in VX2-tumor bearing rabbits (MRT)
The photographs in FIGS. 1 and 2 show MR images of iliac lymph nodes in a rabbit with an intramuscularly implanted VX2 tumor before imaging and up to 24 hours after intravenous administration of the title substance Gd 50 μmol / kg body weight of Example 1d). Indicates. T1-weighted turbo spin echo images show a strong signal rise in healthy lymph node tissue at an early time point after contrast agent administration (15-60 min pi). A band where there was no signal increase in the lymph node was diagnosed as metastasis and confirmed histologically (H / E staining of lymph node section) (FIG. 1).

  Surprisingly, a clear enhancement (especially surroundings) of the primary tumor can also be seen as early as immediately after administration (FIG. 2). Thereafter (24 hours pi), this enhancement also spreads to the center of the tumor.

Example 34: MRT visualization of arteriosclerotic plaques after intravenous administration of contrast agent in rats The photograph of FIG. 3 shows Example 1d) and implementation in Watanabe rabbits (WHHL rabbits; genetically induced arteriosclerosis). MR images of the aorta 6 to 24 hours after intravenous administration of the title substance Gd 50 μmol / kg body weight of Example 14c and a control animal (white New Zealanders) without arteriosclerosis are shown. T1-weighted reverse recovery image (IR-TFL, TR / TE / TI = 300 / 4.0 / 120 ms, α20 °) shows a strong signal increase in arteriosclerotic plaques in WHHL rabbits, but a baseline image or normal Not shown in vessel wall of control animals. Plaque localization, particularly in the aortic arch and vascular pathway, was confirmed using Sudan 3 staining. This test could be used to show the stability of the compounds in the present invention as a marker for atherosclerotic plaque.

Example 35: MRT visualization of inflammatory lesions and necrotic areas after intravenous administration of contrast agent in rats For example, the photograph in FIG. 4 shows the rat after Example 14c title substance Gd 50 μmol / kg body weight after intravenous administration MR images of inflammatory muscle lesions and necrotic areas at each time point are shown. Inflammation / necrosis was induced by 20 minutes stimulation with a xenon lamp following intravenous administration of rose bengal (20 mg / kg; 24 hours before contrast agent administration). T1-weighted turbo spin echo images (1.5T; sequence: T1-TSE; TR451ms, TE8.7ms) show a strong signal rise in tissues that showed early inflammatory changes (pi within 60 minutes), 24 hours p. i. Sometimes it shows a delayed signal rise in the necrosis of the central part.

Example 36: MRT visualization of lymph nodes after intravenous administration of contrast medium in rats For example, the photographs are the title substance of Example 5), the title substance of Example 14c) and the title substance of Example 15c) in rats. MR images of lymph nodes at each time point after intravenous administration of Gd 50 μmol / kg body weight are shown. T1-weighted turbo spin echo images (1.5T; sequence: T1-TSE; TR451ms, TE8.7ms) show a strong signal rise in functional lymph node tissue at an early time point (pi within 60 minutes).

The photograph of FIG. 1 shows MR images of lymph nodes of the iliac bones before imaging and 24 hours after intravenous administration of the title substance Gd 50 μmol / kg body weight of Example 1d) in rabbits with intramuscularly implanted VX2 tumors. . The photograph in FIG. 2 shows MR images of lymph nodes of the iliac bone in a rabbit having a VX2 tumor implanted intramuscularly before imaging of the title substance Gd 50 μmol / kg body weight of Example 1d) and up to 24 hours after intravenous administration. . The photograph in FIG. 3 shows the title substance Gd of 50 μmol / body weight in a Watanabe rabbit (WHHL rabbit; genetically induced arteriosclerosis) of Example 1d) and Example 14c and a control animal (white New Zealanders) without arteriosclerosis. An MR image of the aorta 6 to 24 hours after intravenous administration of kg is shown. The photograph in FIG. 4 shows MR images of inflammatory muscle lesions and necrotic areas at various time points after intravenous administration of the title substance Gd 50 μmol / kg body weight of rat Example 14c. The photograph of FIG. 5 shows MR images of lymph nodes at each time point after intravenous administration of the title substance of Example 5), the title substance of Example 14c) and the title substance Gd of Example 15c) of 50 μmol / kg body weight in rats. Show.

Claims (22)

Formula I

[Wherein R represents either a monosaccharide or an oligosaccharide group bonded via 1-OH;
In this case, Q is
δ-CO- (CH ₂ ) _{n ″} -ε
δ-NH- (CH ₂ ) _{n ″} -ε
δ− (CH ₂ ) _m −ε
(Where
n ″ is an integer from 1 and 5;
m is an integer from 1 and 6;
δ represents a binding site to the linker L, and ε represents a binding site to the group R. )
Means a group selected from
Or R means one of the following, where Q means a direct bond and R is
In the formula, R ¹ means a hydrogen atom or a metal ion equivalent of 20 to 29, 31 to 33, 37 to 39, 42 to 44, 49 or 57 to 83 atoms,
The groups R ² , R ³ , R ⁴ , U and U ¹ are a complex K of the general formulas II to V having the meaning indicated below,
Or —CO—, —NR ⁷ — or a carbon chain having 1 to 30 C atoms bonded to the linker L via a direct bond,
(This may be linear or branched, saturated or unsaturated,
This may optionally include 1 to 10 oxygen atoms, 1 to 5 —NHCO groups, 1 to 5 —CONH groups, 1 to 2 sulfur atoms, 1 to 5 —NH groups, or 1 to 2 phenylene groups. The group may optionally be substituted by 1 to 2 OH groups, 1 to 2 NH ₂ groups, 1 to 2 —COOH groups, or 1 to 2 —SO ₃ H groups, and Optionally substituted by 1 to 10 OH groups, 1 to 5 —COOH groups, 1 to 2 SO ₃ H groups, 1 to 5 NH ₂ groups or _{1 to} 5 C ₁ -C ₄ -alkoxy groups. ,
R ⁷ represents H or C ₁ -C ₄ -alkyl. )
Means a polar group selected from
R _f is a perfluoro linear or branched carbon chain having the formula —C _n F _2n E, where E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n is 4-30. Represents an integer of
K represents the general formula II

(Where
R ¹ means a hydrogen atom or a metal ion equivalent of 21 to 29, 31 to 33, 37 to 39, 42 to 44, 49 or 57 to 83 atoms,
However, at least 2 R ¹ represents a metal ion equivalent,
R ² and R ³ each independently represent hydrogen, C ₁ -C ₇ -alkyl, benzyl, phenyl, —CH ₂ OH or —CH ₂ OCH ₃ ;
U represents —C ₆ H ₄ —O—CH ₂ —ω, — (CH ₂ ) _1-5 —ω, a phenylene group, —CH ₂ —NHCO—CH ₂ —CH (CH ₂ COOH) —C ₆ H _4. —Ω—, —C ₆ H ₄ — (OCH ₂ CH ₂ ) _0-1 —N (CH ₂ COOH) —CH ₂ —ω or optionally one or more oxygen atoms, 1 to 3 —NHCO groups Or C ₁ -C ₁₂ -alkylene _or- (CH ₂ ) _7-12 -C interrupted by 1 to 3 —CONH— groups and / or substituted by 1 to 3 — (CH ₂ ) _0-5 COOH groups ₆ represents a H ₄ —O group, and ω represents a binding site to —CO—. )
Or general formula III

(Wherein R ¹ has the above-mentioned meaning, R ⁴ represents hydrogen or a metal ion equivalent listed under R ¹ , and U ¹ represents —C ₆ H ₄ —O—CH ₂ —ω— Or represents a — (CH ₂ ) _{p ′} — group, ω represents a binding site to —CO—, and p ′ is an integer of 1 to 4.
Or general formula IV

(In the formula, R ¹ and R ² have the above-mentioned meanings.)
Or general formula VA or VB

(Wherein R ¹ has the above-mentioned meaning.)
Or general formula VI

(Wherein R ¹ has the above-mentioned meaning.)
Or general formula VII

(In the formula, R ¹ and U ¹ have the above-mentioned meanings, and ω means a binding site to —CO—.)
Or general formula VIII

Wherein R ¹ has the above meaning,
U ² represents a straight chain or branched chain, saturated or unsaturated C ₁ -C ₂₀ alkylene group, which may optionally be an imino, phenylene, phenyleneoxy, phenyleneimino, amide, hydrazide, carbonyl, ester group, (one Or) containing oxygen, sulfur and / or nitrogen atoms, optionally substituted by hydroxy, mercapto, oxo, thioxo, carboxy, carboxyalkyl, ester (s) and / or amino groups,
The free acid group optionally present in the group K can optionally be present as an organic and / or inorganic base or a salt of an amino acid or amino acid amide,
L represents a group selected from the following groups IXa) to IXc):

(In the formula, n ′ and m ′ each independently represent an integer of 0 to 4, m ′ + n ′ ≧ 1, and
R ⁸ and R ^{8 ′} are each independently either —H or —OH, and when m ′ + n ′> 1, — (CR ⁸ R ^{8 ′} ) groups are the same or different. You can
W is either a direct bond, -O- or a phenylene group, which may be optionally substituted by 1 to 4 hydroxy groups;
q ′ is one of 1, 2, 3 or 4;
α means the binding site of L to complex K, β is the binding site of L to group Q, and γ is the binding site of L to group X. ))
Represents a metal complex of
X is the formula (VI)

Wherein Y represents a direct bond, a —CO— group or an NR ⁶ group,
R ⁶ represents —H or a linear or branched, saturated or unsaturated C ₁ -C ₁₅ carbon chain, which includes 1 to 4 O atoms, 1 to 3 NHCO groups, 1 to CONH groups 1 to May be interrupted by three, 1-2 SO ₂ groups, 1-2 sulfur atoms, 1-3 NH groups or 1-2 phenylene groups,
This may optionally be substituted by 1 to 2 OH groups, 1 to 2 NH ₂ groups, 1 to 2 —COOH groups or 1 to 2 —SO ₃ H groups,
This may optionally be 1 to 10 OH groups, 1 to 5 —COOH groups, 1 to 2 —SO ₃ H groups, 1 to 5 NH ₂ groups, or _{1 to} 5 C ₁ -C ₄ -alkoxy groups. Replaced by
G means either —O— or —SO ₂ —;
s and s ′ each independently represent either 1 or 2, t represents either 0 or 1,
ρ represents the binding site of X to L, and ζ represents the binding site of X to R _f . )
Represents a group of )] Perfluoroalkyl-containing complex having a nitrogen-containing linker structure. The metal complex according to claim 1, wherein the metal ion equivalent R ¹ is an element having 21 to 29, 39, 42, 44 or 57 to 83 atoms. The metal complex according to claim 1, wherein the metal ion equivalent R ¹ is an element having an atomic number of 27, 29, 31 to 33, 37 to 39, 43, 49, 62, 64, 70, 75 and 77.   The metal complex according to any one of claims 1 to 3, wherein R represents a monosaccharide group having 5 to 6 C atoms or a desoxy compound thereof, preferably glucose, mannose or galactose. R is

And a group selected from the complex of formula (II), wherein R ¹ , R ² , R ³ and U are defined as in claim 1, p is 1, 2, 3, 4, 5, The metal complex according to any one of claims 1 to 3, wherein the metal complex is any one of 6, 7, 8, and 9.   The metal complex according to claim 1, wherein K represents a metal complex of the general formula II. R ² and R ³ are each independently hydrogen or C ₁ -C ₄ - refers to an alkyl, a metal complex according to claim 6. E in formula -C _n F _2n E means a fluorine atom, a metal complex according to any one of claims 1 to 7.   The metal complex according to claim 1, wherein L in the general formula I represents a lysine group (Vc).   The metal complex according to claim 1, wherein L in the general formula I represents a diamine group (Va) or (Vb). 11. U in metal complex K represents —CH ₂ or —C ₆ H ₄ —O—CH ₂ —ω, wherein ω represents a binding site to —CO—. 2. The metal complex according to item 1.   Use of the metal complex according to claim 2 for the production of a contrast agent for use in NMR and x-ray diagnostics.   Use of a metal complex according to claim 12 for the production of contrast agents for infarct and necrosis images.   Use of the metal complex according to claim 3 for the manufacture of a contrast agent for use in radiodiagnosis and radiotherapy.   Use of the metal complex according to claim 2 for the production of a contrast medium for lymphatic imaging for diagnosing changes in the lymphatic system.   Use of a metal complex according to claim 2 for the manufacture of a contrast medium for the diagnosis of inflammatory diseases.   Use of a metal complex according to claim 2 for the production of a contrast agent for visualizing atherosclerotic plaques.   Use of the metal complex according to claim 2 for the production of a contrast medium for the diagnosis of cardiovascular diseases.   Use of the metal complex according to claim 2 for the production of a contrast agent for tumor imaging.   Use of the metal complex according to claim 2 for the production of a contrast agent for blood pool images.   12. A pharmaceutical formulation comprising at least one physiologically compatible compound according to any one of claims 1 to 11 and optionally an additive commonly used in galenical formulations. Formula I

(K means a metal complex of the general formulas II to IV according to claim 1, L, Q, X, R and _Rf have the meaning according to claim 1.)
In the method for producing a perfluoroalkyl-containing metal complex having a nitrogen-containing linker structure of
Formula IIa

(In the formula, R ⁵ means a metal ion equivalent of 21 to 29, 31 to 33, 37 to 39, 42 to 44, 49 or 57 to 83, or a carboxyl protecting group, and R ² , R ³ and U Has the above meaning.)
Or a carboxylic acid of the general formula IIIa

(In the formula, R ⁴ , R ⁵ and U ¹ have the above-mentioned meanings.)
Or a carboxylic acid of the general formula IVa

(In the formula, R ⁵ and R ² have the above-mentioned meanings.)
A carboxylic acid of the general formula Va or Vb

(Wherein R ⁵ has the above meaning.)
Or a carboxylic acid of the general formula VIa

(Wherein R ⁵ has the above meaning.)
Or a carboxylic acid of the general formula VIIa

(Wherein R ⁵ and U ¹ have the above meanings.)
Carboxylic acid,
Or general formula VIIIa

Wherein R ⁵ has the above meaning,
U ² is defined as in claim 1. )
A carboxylic acid of the general formula XI in an optionally activated form

(Wherein L, R, R _f , Q and X have the meanings indicated in the above claims) with an amine in a coupling reaction, optionally cleaving any protecting groups present To form a metal complex of the general formula I,
Or
If R ⁵ means a protecting group, as is known in the art, in a subsequent step, after cutting these protecting groups, atoms 21～29,31～33,37～39,42～44 , 49 or 57-83 with at least one metal oxide or metal salt of the element and then, if desired, the optionally present acidic hydrogen atom as a cation of an inorganic and / or organic base, amino acid or amino acid amide A method comprising:

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