JP2006514664A - Benzene derivatives substituted with macrocycles as trimers - Google Patents

Abstract

Metal complexes of the general formula (I) [wherein Hal represents bromine or iodine and A ¹ and A ² have different meanings] are suitable as contrast agents.

Description

  The present invention relates to the objects characterized in the claims: novel trimers, macrocyclic substituted triiodo and tribromobenzene derivatives, their preparation and as contrast agents in X-ray and MRT diagnostics. Regarding use.

In the last decade, impressive progress has been made in diagnostic imaging. Imaging technologies such as DAS, CT and MRT have evolved into tools that cannot be abandoned by standard in diagnostics and interventional radiology, and today offer spatial resolutions of less than 1 mm. The applicability of these techniques is further enhanced by the use of contrast agents. This widespread acceptance and acceptance of contrast agents in X-ray diagnostics today is due to the introduction of non-ionic monomeric triiodo aromatics in the 80's, and isotonic dimeric iodine aromatics introduced in the 90's Can be attributed to Both types of compounds reduced the frequency of contrast-related side effects to 2-4% (Bush WH, Swanson DP: Acute reactions to intravascular contrast media: Types, risk factors, recognition and specific treatment. AJR 157 , 1153-1161, 1991. Rydberg J., Charles J., Aspelin P .: Frequency of late allergy-like adverse reactions following injection of intravascular non-ionic contrast media. Acta Radiologica 39 , 219-222, 1998). The use of contrast agents in combination with state-of-the-art imaging techniques today extends from tumor detection to quantitative measurements of physiological factors such as organ permeability or perfusion for high resolution angiography. It is the concentration (in this case of iodine atoms) of the X-ray contrast agent that is decisive for contrast and detection sensitivity. Despite further development of technology, the concentration required for medical diagnosis or the dose to be applied could not be reduced. For example, in a classic CT examination, 100 g or more of substance per patient is injected.

Despite the improved compatibility of X-ray contrast agents with the introduction of nonionic triiodobenzene, the side effects are still high. Based on the very high number of examinations in the X-ray diagnosis of millions per year, therefore 10,000 patients are applicable. These contrast-related side effects range from mild reactions such as nausea, dizziness, vomiting and urticaria to severe reactions such as bronchospasm and renal failure, and reactions such as shock or even death. Yes. Fortunately, these severe cases are extremely rare and are observed with a frequency of only 1/200000 (Morcos SK, Thomsen HS: Adverse reactions to iodinated contrast media. Eur Radiol 11 , 1267-1275, 2001). .

The frequency of these side effects, which are also observed as pseudoallergic contrast side effects, is increased about three times in the case of atopic patients and five times in the case of patients with a history of contrast side effects. Asthma increases the risk of severe contrast-related side effects by a factor of 6 in the case of non-ionic contrast agents (Thomsen HS, Morcos SK: Radiographic contrast media. BJU 86 (Suppl1), 1-10, 2000. Thomsen HS, Dorph S .: High-osmolar and low-osmolar contrast media.An update on frequency of adverse drug reactions.Ata Radiol 34 , 205-209, 1993.Katayama H, Yamaguchi K., Kozuka T., Takashima T., Seez P ., Matsuura K .: Adverse reactions to ionic and nonionic contrast media.Radology 175 , 621-628, 1990.Thomsen HS, Bush Jr WH: Adverse effects on contrast media. Incidence, prevention and management.Drug Safety 19 : 313-324 , 1998). In these situations, X-ray diagnostic inspectors have become increasingly frequent in computer tomography, but also in interventional radiology as well as in DSA, with Gd containing no iodine instead of the classic triiodoaromatic compounds. -Use chelate (Gierada DS, Bae KT: Gadolinium as CT contrast agent: Assessment in a porcine model.Radiology 210 , 829-834, 1999. Spinosa DJ, Matsumoto AH, Hagspiel KD, Angle JF, Hartwell GD: Gadolinium- Radiology 223 , 319- based contrast agents in angiography and interventional radiology.AJR 173; 1403-1409, 1999.Spinosa DJ, Kaufmann JA, Hartwell GD: Gadolinium chelates in angiography and interventional radiology: A useful alternative to iodinated contrast media for angiography. 325, 2002). This is supported, on the one hand, by the very good compatibility of the metal chelates used in MRT, but also by the known fact that lanthanides do not pass X-rays as well. Since gadolinium and other lanthanides exhibit greater absorption than iodine, especially at higher X-ray voltages / energy compared to iodine, they are in principle suitable for X-ray diagnostics as contrasting elements (Schmitz S. , Wagner S., Schuhmann-Giampieri G., Wolf KJ: Evaluation of gadobutrol in an rabbit model as a new lanthanide contrast agent for computer tomography. Invest. Radiol. 30 (11 ): 644-649, 1995).

The Gd-containing chelates originally used in the MRTs mentioned are likewise sufficiently water-soluble and stand out for excellent compatibility. Compared to iodine-containing / non-ionic contrast agents, the rate of mild pseudoallergic reactions is significantly reduced, the rate of fatal reactions is extremely rare and is shown at 1/1000000 ( Runge VM: Safety of approved MR contrast media for intravenous injection. J. Magn Reson Imaging 12 , 205-213, 2000). Pseudoallergic reactions differ from other contrast-related side effects, for example, renal compatibility is rather independent of the dose administered. Correspondingly, even the lowest dose can already cause a pseudoallergic reaction.

  Substances that combine the advantages of both chemically distinct compound types are desirable.

  The unusually high hydrophilicity of metal chelates supports a small percentage of incompatibility. Iodoaromatic compounds have lipophilicity (a larger partition coefficient between butanol / water) that is 100 to 200 times higher than metal chelates.

Previously known metal chelates are not optimal for X-ray diagnostics based on the low substance concentration and the low specific content of the imaging metal of the whole molecule (Albrecht T., Dawson P .: Gadolinium-DTPA as X-ray contrast medium in clinical studies. BJR 73 , 878-882, 2000). A newer clue to solving this problem describes the preparation of complex metal complexes, in which triiodo aromatic compounds are covalently bound to open chain or macrocyclic metal complexes (US 5,324,503, US 5,403,576, WO 93/16375, WO 00/75141, WO 97/01359, WO 00/71526, US 5,660,814). Because of their slight hydrophilicity and high viscosity, however, these cannot be applied at sufficient concentrations and acceptable volumes.

  The aim is to produce compounds that have sufficient hydrophilicity—comparable to that of Gd chelates—and additionally have a high concentration of elements that give contrast. A clearly higher value would be desirable over a metal chelate that is about 25% (g / g). Furthermore, very good water solubility must be provided at higher concentrations. Highly concentrated solutions, in addition to their good pharmacological properties, must also exhibit a viable viscosity and low osmotic pressure.

  This problem is solved by the present invention.

  Formula I

［式中、
Halは臭素又はヨウ素を表し、
Ａ^１は基
−ＣＯＮＲ^１−（ＣＨ_２）_ｎ−ＮＲ^２−（ＣＯ−ＣＨＺ^１−ＮＨ）_ｍ−ＣＯ−ＣＨＺ^２−Ｋ、
−ＣＯＮＲ^１−（ＣＨ_２）_ｐ−（ＣＯＮＲ^２ＣＨ_２）_ｍ−ＣＨＯＨ−ＣＨ_２−Ｋ、
−ＣＨ_２Ｏ−（ＣＨ_２）_ｐ−ＣＨＯＨ−ＣＨ_２−Ｋ、
−ＣＨ_２Ｏ−（ＣＨ_２）_ｎ−ＮＲ^１−（ＣＯ−ＣＨＺ^１−ＮＨ）_ｍ−ＣＯ−ＣＨＺ^２−Ｋ、
−ＣＨ_２−ＮＲ^１−ＣＯ−（ＣＨＺ^１−ＮＨ−ＣＯ）_ｍ−ＣＨＺ^２−Ｋ
を表し、
Ａ^２はＡ^１と同じ意味を有するか、又はＡ^１が一番最初に挙げた意味を有する場合には基−ＮＲ^１−ＣＯ−（ＮＲ^１）_ｍ−（ＣＨ_２）_ｐ−ＮＲ^２−（ＣＯ−ＣＨＺ^１−ＮＨ）_ｍ−ＣＯ−ＣＨＺ^２−Ｋも表してよく、
ここで、Ｒ^１及びＲ^２は独立して水素原子、Ｃ_１〜Ｃ_２−アルキル基又はモノヒドロキシ−Ｃ_１〜Ｃ_２−アルキル基を表し、
Ｚ^１及びＺ^２は互いに独立して水素原子又はメチル基を表し、
ｎは２〜４の数を表し、
ｍは０又は１の数を表し、かつ
ｐは１〜４の数を表し、
Ｋは式Ｉ_Ａ

[Where:
Hal represents bromine or iodine,
A ¹ is a group —CONR ¹ — (CH ₂ ) _n —NR ² — (CO—CHZ ¹ —NH) _m —CO—CHZ ² —K,
_{^{-CONR 1 - (CH 2) p}} - (CONR 2 CH 2) m -CHOH-CH 2 -K,
_{-CH 2 O- (CH 2) p} -CHOH-CH 2 -K,
^{_{-CH 2 O- (CH 2) n}} -NR 1 - (CO-CHZ 1 -NH) m -CO-CHZ 2 -K,
—CH ₂ —NR ¹ —CO— (CHZ ¹ —NH—CO) _m —CHZ ² —K
Represents
A ² is either have the same meaning as ^{A 1,} or the group ^-NR 1 -CO- in case have the ^{meanings A 1} is very first-mentioned _{^{(NR 1) m - (CH}} 2) p -NR 2 - (CO—CHZ ¹ —NH) _m —CO—CHZ ² —K may also be represented,
Here, R ¹ and R ² independently represent a hydrogen atom, a C ₁ -C ₂ -alkyl group or a monohydroxy-C ₁ -C ₂ -alkyl group,
Z ¹ and Z ² each independently represent a hydrogen atom or a methyl group,
n represents a number from 2 to 4,
m represents a number of 0 or 1, and p represents a number of 1 to 4,
K is the formula _{I A}

｛式中、Ｘは水素原子又は原子番号２０〜２９、３９、４２、４４又は５７〜８３の金属イオン等価物(Metallionenaequivalents)の意味である｝で示される大環状化合物を表し、但し、少なくとも２つのＸは金属イオン等価物を表し、かつ場合により存在している遊離カルボキシ基は場合により有機及び／又は無機の塩基又はアミノ酸又はアミノ酸アミドの塩として存在する］で示される本発明による金属錯体は、極めて良好な溶解度及びＧｄキレートの分配係数に匹敵しうる分配係数を示す。さらに新規化合物はコントラストを与える元素の高い比含量、低い粘度及び浸透圧重量モル濃度、ひいては良好なトレランス／適合性を有するので、これらはレントゲン−及びＭＲ−撮像用の造影剤として卓越して適している。

{Wherein X represents a hydrogen atom or a macrocyclic compound having the meaning of a metal ion equivalent of an atomic number of 20-29, 39, 42, 44, or 57-83}, provided that at least 2 X represents a metal ion equivalent, and the optionally present free carboxy group is optionally present as a salt of an organic and / or inorganic base or amino acid or amino acid amide]. Shows a very good solubility and a partition coefficient comparable to that of Gd chelates. In addition, the new compounds have a high specific content of contrasting elements, low viscosity and osmolality and thus good tolerance / compatibility, making them outstandingly suitable as contrast agents for X-ray and MR imaging. ing.

Preferably Hal represents iodine, R ¹ and R ² represent hydrogen and a methyl group, n represents a number of 2, and p represents a number of 1.

Exemplary groups A ¹ are:
_{-CONH (CH 2) 2; 3} NHCOCH 2 NHCOCH (CH 3) -,
_{-CONH (CH 2) 2; 3} NHCOCH 2 NHCOCH 2 -,
_{-CONH (CH 2) 2; 3} NHCOCH 2 -,
_{-CONH (CH 2) 2; 3} NHCOCH (CH 3) -,
_{-CONHCH 2 CH (OH) CH 2} -,
_{-CON (CH 3) CH 2 CH} (OH) CH 2 -,
_{-CH 2 OCH 2 CH (OH)} CH 2 -,
_{-CONHCH 2 CONHCH 2 CH (OH)} CH 2 -,
-CH ₂ NHCOCH ₂ -,
_{-CH 2 NHCOCH (CH 3) -} ,
-CH ₂ NHCOCH ₂ NHCOCH ₂ -,
_{-CH 2 NHCOCH 2 NHCOCH (CH 3} ) -,
_{-CH 2 O (CH 2) 2} NHCOCH 2 -,
_{-CON (CH 2 CH 2 OH (} CH 2) 2 NHCOCH 2 -,
_{-CH 2 O (CH 2) 2} N (CH 2 CH 2 OH) COCH 2 -.

Illustrative groups A ² are:
_{-NHCOCH 2 NHCOCH 2 NHCOCH (CH 3} ) -,
-NHCOCH ₂ NHCOCH ₂ NHCOCH ₂ -,
-NHCOCH ₂ NHCOCH ₂ -,
_{-NHCOCH 2 NHCOCH (CH 3) -} ,
_{-N (CH 3) COCH 2 NHCOCH} 2 -,
_{-NHCONH (CH 2) 2 NHCONH 2} -,
_{-NHCOCH 2 N (CH 2 CH 2} OH) COCH 2 -,
_{-N (CH 3) COCH 2 N} (CH 2 CH 2 OH) COCH 2 -.

The compounds according to the invention of general formula I can be prepared by methods known to those skilled in the art, for example a)

で示されるトリヨード−又はトリブロモ芳香族化合物を本来公知の方法で一般式ＩＩＩ

A triiodo- or tribromoaromatic compound represented by the general formula III

［式中、
Ｃ^ｘＯは−ＣＯＯＨ−又は活性化されたカルボキシル基を表し、
Ｗは保護基又は−ＣＨ_２ＣＯＯＸ′−基｛式中、Ｘ′はＸ又は保護基の意味である｝を表し、かつ−Ｙ^１−ＮＲ^１−ＣＯ−Ｂ^１−は−ＣＯ−ＮＲ^１−（ＣＨ_２）_ｎ−ＮＲ^２−（ＣＯ−ＣＨＺ^１−ＮＨ）_ｍ−ＣＯ−ＣＨＺ^２−又は−ＣＨ_２−Ｏ−（ＣＨ_２）_ｎ−ＮＲ^１−（ＣＯ−ＣＨＺ^１−ＮＨ）_ｍ−ＣＯ−ＣＨＺ^２−の意味の基Ａ^１を表し、かつＹ^２−ＮＲ^１−ＣＯ−Ｂ^１はＹ^１−ＮＲ^１−ＣＯ−Ｂ^１を表すか又はＹ^１−ＮＲ^１−ＣＯ−Ｂ^１が一番最初に挙げた意味を有する場合には−ＮＲ^１−ＣＯ−（ＮＲ^１）_ｍ（ＣＨ_２）_ｐ−ＮＲ^２−（ＣＯ−ＣＨＺ^１−ＮＨ）_ｍ−ＣＯ−ＣＨＺ^２−も表し、ここでＢ^１は−ＣＯ−とＫとの間の１番目又は２番目の（Ｋから見て）カルボニル基上にある基を意味し、かつＹ^１もしくはＹ^２はイミノ基が１つだけ減少されたリンカー基の不足する基を表す］で示される大環状化合物と反応させ、引き続いて場合により保護基Ｗを除去し、かつ基ＣＨ_２ＣＯＯＸを本来公知の方法で導入するか、もしくはＸ′を場合により表す保護基を除去し、引き続いて本来公知の方法で原子番号２０〜２９、３９、４２、４４又は５７〜８３の元素の金属酸化物又は金属塩と反応させることによるか、又は
ｂ）一般式ＩＶ

[Where:
C ^x O represents —COOH— or an activated carboxyl group,
W represents a protecting group or a —CH ₂ COOX′— group (where X ′ represents X or a protecting group), and —Y ¹ —NR ¹ —CO—B ¹ — represents —CO—NR ¹ — (CH ₂ ) _n —NR ² — (CO—CHZ ¹ —NH) _m —CO—CHZ ² — or —CH ₂ —O— (CH ₂ ) _n —NR ¹ — (CO—CHZ ¹ —NH) _m Represents the group A ^{1 in} the meaning —CO—CHZ ² — and Y ² —NR ¹ —CO—B ¹ represents Y ¹ —NR ¹ —CO—B ¹ or Y ¹ —NR ¹ —CO—B ^{1 -NR} 1 -CO- if it has the meaning most initially mentioned _{^{(NR 1) m (CH 2}} ) p -NR 2 - (CO-CHZ 1 -NH) m -CO-CHZ 2 - also expressed, wherein B ¹ represents (as viewed from K) 1 or second of between -CO- and K near the carbonyl group It refers to the group, and Y ¹ or Y ² is reacted with a macrocyclic compound represented by a group of the lack of linker groups that are reduced by one imino group, optionally removing the protecting group W subsequently And the group CH ₂ COOX is introduced in a manner known per se, or the protective group optionally representing X ′ is removed and subsequently atom numbers 20-29, 39, 42, 44 or 57—in a manner known per se. By reacting with a metal oxide or metal salt of the element 83, or b) with the general formula IV

で示されるトリヨード−又はトリブロモ芳香族化合物を本来公知の方法で一般式Ｖ

A triiodo- or tribromo aromatic compound represented by the general formula V

［式中、−Ｃ^ｘＯ及びＸ′は前記の意味を表し、かつ−ＣＯ−ＮＲ^１−Ｙ^３は−ＣＯＮＲ^１−（ＣＨ_２）_ｐ−（ＣＯＮＲ^２ＣＨ_２）_ｍ−ＣＨ（ＯＨ）ＣＨ_２−の意味の基Ａ^１を表し、それゆえＹ^３は−ＮＲ^１−（ＣＨ_２）_ｐ−（ＣＯＮＲ^２ＣＨ_２）_ｍ−ＣＨ（ＯＨ）ＣＨ_２−の意味を表す］で示される大環状化合物と反応させ、引き続いてＸ′を場合により表す保護基を除去し、その後本来公知の方法で原子番号２０〜２９、３９、４２、４４又は５７〜８３の元素の金属酸化物又は金属塩と反応させることによるか、又は
ｃ）一般式ＶＩ

[Wherein, —C ^x O and X ′ represent the above meanings, and —CO—NR ¹ —Y ³ represents —CONR ¹ — (CH ₂ ) _p — (CONR ² CH ₂ ) _m —CH (OH) Represents a group A ^{1 in} the meaning of CH ₂ — and therefore Y ³ represents the meaning of —NR ¹ — (CH ₂ ) _p — (CONR ² CH ₂ ) _m —CH (OH) CH ₂ —. Reacting with the macrocycle and subsequently removing the protective group optionally representing X ′, and thereafter metal oxides or metals of the atomic number 20-29, 39, 42, 44 or 57-83 in a manner known per se By reacting with a salt, or c) general formula VI

［式中、
Ａ^１は基

[Where:
A ¹ is the group

を表す］で示されるトリヨード−又はトリブロモ芳香族化合物を本来公知の方法で一般式ＶＩＩ

A triiodo- or tribromo aromatic compound represented by the general formula VII

［式中、Ｗ′は水素原子又は保護基を表す］で示される環状化合物と反応させて、（場合により存在している保護基を除去し、引き続いて本来公知の方法で基−ＣＨ_２ＣＯＯＸを導入した後で）一般式Ｉの金属錯体｛ここでＡは基−ＣＨ_２−Ｏ−（ＣＨ_２）_ｐ−ＣＨＯＨ−ＣＨ_２−の意味である｝に変換させることによるか、又は
ｄ）一般式ＶＩＩＩ

[Wherein W ′ represents a hydrogen atom or a protecting group] is reacted with a cyclic compound (removing an optionally present protecting group, followed by a group —CH ₂ COOX in a manner known per se). Or by conversion to a metal complex of the general formula I, where A is the meaning of the group —CH ₂ —O— (CH ₂ ) _p —CHOH—CH ₂ —, or d) Formula VIII

［式中、Nucleofugは脱離基(nucleofuge Gruppe)を表す］で示されるトリヨード−又はトリブロモ芳香族化合物を本来公知の方法で一般式ＩＸ

[Wherein Nucleofug represents a nucleofuge Gruppe] A triiodo- or tribromoaromatic compound represented by the general formula IX

［式中、
Ｒ^１及びＷは前記の意味を表し、かつＢ^２は基−（ＣＨＺ^１−ＮＨＣＯ）_ｍ−ＣＨＺ^２−を表す］で示される大環状化合物と反応させ、引き続いてａ）のもとに記載されたようにさらに行い、その結果、一般式Ｉの金属錯体｛その際にＡ^１は基−ＣＨ_２−ＮＲ^１−ＣＯ−（ＣＨＺ^１−ＮＨＣＯ）_ｍ−ＣＨＺ^２の意味である｝が得られ、その際に引き続いて場合によりこうしてａ）〜ｄ）により得られる一般式Ｉの金属錯体中に依然として存在している酸性水素原子が無機又は有機の塩基、アミノ酸又はアミノ酸アミドのカチオンにより置換されることによって製造されうる。

[Where:
R ¹ and W are as defined above, and B ² represents a macrocycle represented by the group — (CHZ ¹ —NHCO) _m —CHZ ² —] and subsequently described under a) As a result, a metal complex of the general formula I {where A ¹ is the meaning of the group —CH ₂ —NR ¹ —CO— (CHZ ¹ —NHCO) _m —CHZ ² ) is obtained. In this case, the acidic hydrogen atoms still present in the metal complexes of the general formula I thus obtained according to a) to d) are optionally replaced by cations of inorganic or organic bases, amino acids or amino acid amides. Can be manufactured.

As amino protecting group W, benzyloxycarbonyl-, t-butoxycarbonyl-, trifluoroacetyl-, fluorenylmethoxycarbonyl-, benzyl-, formyl-, 4-methoxybenzyl-, 2, 2,2-trichloroethoxycarbonyl-, phthaloyl-, 1,2-oxazoline-, tosyl-, dithiasuccinoyl-, allyloxycarbonyl-, sulfate-, pent-4-enecarbonyl-, 2-chloroacetoxymethyl ( Or -ethyl) benzoyl-, tetrachlorophthaloyl-, alkyloxycarbonyl groups [Th. W. Greene, PGM Wuts, Protective Groups in Organic Syntheses, 2nd edition, John Wiley and Sons (1991), 30-385; E. Meinjohanns et al., J. Chem. Soc. Pekin Trans 1, 1995, 405; U. Ellensik et al., Carbohydrate Research 280 , 199 6, 251; R. Madsen et al., J. Org. Chem. 60 , 1995, 7920; RR Schmidt, Tetrahedron Letters 1995, 5343].

Cleavage of the protecting group is carried out by methods known to those skilled in the art (e.g. E. Wuensch, Methoden der Org. Chemie, Houben-Weyl, XV / 1 , 4th edition, 1974, 315) By alkali saponification of the ester with an alkali in an aqueous-alcoholic solution at a temperature of 0 ° C. to 50 ° C., acid saponification with a mineral acid or with trifluoroacetic acid in the case of the Boc-group.

  An activated carboxyl group is understood to be a carboxyl group as defined above that has been derivatized to facilitate reaction with an amine. It is known which groups can be used for activation and reference can be made, for example, to M. and A. Bodanszky, “The Practice of Peptide Synthesis”, Springerverlag 1984. Examples are adducts or activated esters of carboxylic acids and carbodiimides, such as hydroxybenzotriazole esters, acid chlorides, N-hydroxysuccinimide esters,

である。好ましくは４−ニトロフェニルエステル及びＮ−ヒドロキシスクシンイミドエステルである。

It is. 4-Nitrophenyl ester and N-hydroxysuccinimide ester are preferred.

  Activated esters of the above compounds are prepared as known to those skilled in the art. Also N-hydroxysuccinimide, for example:

の相応して誘導体化されたエステルとの反応も可能である（Hal＝ハロゲン）。

It is also possible to react with the correspondingly derivatized ester (Hal = halogen).

  In general, all conventional activation methods for carboxylic acids known in the state of the art can be used. Activation of carboxylic acid is performed by a conventional method. Examples of suitable activating reagents are dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide-hydrochloride (EDC), benzotriazol-1-yloxytris (dimethylamino) -Phosphonium hexafluorophosphate (BOP) and O- (benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), preferably DCC. The addition of O-nucleophilic catalysts such as N-hydroxysuccinimide (NHS) or N-hydroxybenzotriazole is also possible.

As a leaving group (Nucleofug), advantageously a group:
F, Cl, Br, I, -OTs, -OMs, OH,

が利用される。

Is used.

  When X ′ represents an acid protecting group, a lower alkyl group, an aryl group and an aralkyl group, such as a methyl group, an ethyl group, a propyl group, a butyl group, a phenyl group, a benzyl group, a diphenylmethyl group, a triphenylmethyl group, The bis- (p-nitrophenyl) -methyl group as well as the trialkylsilyl group apply.

  A t-butyl group and a benzyl group are preferred.

  Cleavage of the protecting group can be carried out by methods known to those skilled in the art (e.g. E. Wuensch, Methoden der Org. Chemie, Houben-Weyl, XV / 1, 4th edition, 1974, page 315). Decomposition, alkaline saponification of esters in aqueous-alcoholic solutions at temperatures between 0 ° C. and 50 ° C., acid saponification with mineral acids or with trifluoroacetic acid in the case of t-butyl esters (Protective Groups in Organic Synthesis, Second edition, TW Greene and PGM Wuts, John Wiley and Sons Inc., New York, 1991).

  The introduction of the desired metal ions can be carried out as disclosed in the patent specifications EP 71564, EP 130934 and DE-OS 34 01 052. To do so, the metal oxide or metal salt of the desired element (eg chloride, nitrate, acetate, carbonate or sulfate) is dissolved or suspended in water and / or lower alcohol (eg methanol, ethanol or isopropanol). And reacted with an equimolar amount of solution or suspension of complexing agent.

  Neutralization of the free carboxy groups which are still present in some cases are, for example, sodium, potassium, lithium, magnesium or calcium inorganic bases (eg hydroxides, carbonates or bicarbonates) and / or organic bases, eg Primary, secondary and tertiary amines such as ethanolamine, morpholine, glucamine, N-methyl- and N, N-dimethylglucamine, and basic amino acids such as lysine, arginine and ornithine or naturally neutral or acidic amino acids The amide is used.

  For the production of neutral complex compounds, for example in acidic complex salts in aqueous solution or suspension, they can be added to the desired base as long as the neutral point is achieved. The resulting solution can subsequently be concentrated to dryness in vacuo. Often, neutral salts formed are miscible with water, eg, lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) It is advantageous to obtain crystals which precipitate by the addition of and thus can be easily isolated and well purified. It has been found to be particularly advantageous to add the desired base to the reaction mixture already during complexation, thereby reducing processing steps.

Resulting purified complexes Thus, if pH 6-8 by addition of acid or base by, preferably after adjusting the pH value to about 7, preferably suitable membrane pore size (e.g., Amicon ^(R) YM1, ultrafiltration in Amicon ^{(R) YM3),} for example, suitable Sephadex ^{(R) -} is carried out by HPLC with a gel filtration or by silica gel or reversed-phase material in the gel.

  Purification can also be performed by crystallization from a solvent such as methanol, ethanol, isopropanol, acetone or a mixture thereof with water.

In the case of neutral complex compounds, often the oligomeric complexes are separated via an anion exchanger, for example IRA 67 (OH ⁻ − form) and optionally additionally a cation exchanger, for example for the separation of ionic components. It is advantageous to add via IRC 50 (H ⁺ -form).

The preparation of the compounds of the general formula I according to the invention can be carried out as described above:
a) The reaction of the triiodo- or tribromoaromatic compound of general formula II with the compound of general formula III is carried out by methods of amide formation known to those skilled in the art.

In this case, direct coupling between the free acid of III and the free amine of II was performed using DMF, DMA, THF, dioxane, toluene, chloroform using dehydrating reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, EDC, EEDQ, TBTU, HATU. Or can be carried out in an aprotic solvent such as methylene chloride at a temperature of 0 ° to 50 ° C., or the acid group in the compound of general formula III is first converted to the active ester (See page 11), then the ester is dissolved in a solvent such as DMF, DMA, THF, dioxane, dichloromethane, i-ProOH, toluene, optionally NEt ₃ , pyridine, DMAP, Huenig base, Na ₂ CO _3. Addition of organic or inorganic base such as CaCO ₃ Under reaction, it is reacted with an amine of the general formula II at a temperature of -10 ° to + 70 ° C.

  In some cases it has proved advantageous to produce the metal complex of the general formula III directly and to couple its terminal carboxylic acid under the method listed in WO 98/24775. .

  The preparation of metal complexes is described in WO 98/24774.

The preparation of the compound of general formula II is carried out when Y ² represents Y ¹

で示される化合物を一般式Ａ
ＨＮＲ^１−（ＣＨ_２）_ｍ−ＮＲ^２Ｈ （Ａ）
［式中、Hal、ＣＯ^＊、Ｒ^１、Ｒ^２、ｍは前記の意味を表す］で示されるジアミンと、当業者に公知のアミド形成の方法（上記参照）によりＤＭＦ、ＤＭＡ、ＴＨＦ、ジオキサン、１，２−ジクロロエタン、クロロホルム、ジクロロメタン又はトルエンのような非プロトン性溶剤中で場合によりＮＥｔ_３、ピリジン、ＤＭＡＰ、Huenig塩基、Ｎａ_２ＣＯ_３、Ｋ_２ＣＯ_３、ＣａＣＯ_３のような有機又は無機の塩基の添加下に０℃〜１００℃の温度で反応させることにより行われる。

A compound represented by general formula A
_{^{HNR 1 - (CH 2) m}} -NR 2 H (A)
[Wherein, Hal, CO ^* , R ¹ , R ² , m are as defined above] and amide formation methods known to those skilled in the art (see above) for DMF, DMA, THF, dioxane An organic such as NEt ₃ , pyridine, DMAP, Huenig base, Na ₂ CO ₃ , K ₂ CO ₃ , CaCO ₃ in an aprotic solvent such as 1,2-dichloroethane, chloroform, dichloromethane or toluene, or The reaction is carried out at a temperature of 0 ° C. to 100 ° C. with the addition of an inorganic base.

  In many cases it has proved advantageous to use the diamine itself as a solvent. Sometimes one of both terminal amino groups is used in protected form (eg mono-Boc, mono-Z) and this coupling group is cleaved by methods known to those skilled in the art after coupling has taken place. It may be advantageous (TW Greene, see above).

  Diamines or monoprotected diamines are known from the literature and are commercially available (eg Aldrich, Fluka). Preferably acid chlorides of compounds of the general formula IV are used.

  Compound

の製造はDE 3001292に記載されている。

The manufacture of is described in DE 3001292.

  The corresponding tri-bromine compounds are prepared analogously from tribromoaminoisophthalic acid by the Sandmeyer reaction (CN introduction and subsequent saponification) as described in EP 0073715.

When Y ² is not equal to Y ^1, the following procedure has been found to be useful:
Formula B

［式中、ＣＯ^＊、Halは前記の意味を表す］で示される化合物はまず最初に一般式Ｃ
ＣＯ^＊−（ＣＨＺ^１）−ＮＨ−Ｓｇ （Ｃ）
［式中、ＣＯ^＊、Ｚ^１は前記の意味を表し、かつＳｇはアミノ保護基を表す］で示されるの化合物と反応される。

[In the formula, CO ^* and Hal represent the above-mentioned meanings]
^{CO * - (CHZ 1) -NH} -Sg (C)
[Wherein CO ^* and Z ¹ represent the above-mentioned meanings, and Sg represents an amino-protecting group].

The reaction is already carried out by the method of amide formation described above (Neher et al. Helv. Chim. Acta, 1946 , 1815.).

  Subsequent reaction with the compound of general formula A already as described above, followed by cleavage of the optionally present amino protecting group (see T.W. Greene).

  It has proven advantageous to use acid chlorides of the general formula C.

  If Sg represents a trifluoroacetyl-protecting group, it is cleaved with an excess of diamine of general formula A directly in a one-pot process.

  The compounds of general formula C can be obtained from the literature by known methods.

  For the preparation of urea derivatives, the compound of general formula B is first of the general formula D

で示されるイソシアナートと反応され、ついで前記のように一般式のジアミンとさらに反応される。

And then further reacted with a diamine of the general formula as described above.

  The reaction of the isocyanate is carried out in an aprotic solvent as described above for amide formation. The reaction temperature is 0 ° C to 100 ° C.

  Isocyanate (D) is prepared, for example, as described in Guichard et al., J. Org. Chem., 1999, 8702.

  Compounds of general formula B are described in DE 3001292.

  b) The reaction of the compound of general formula IV with the compound of general formula V is carried out by amide formation methods known to those skilled in the art as already described in detail under a) previously.

  Here too, the acid chloride of compound IV is preferably used.

  Compounds of general formula V are of general formula E

［式中、Ｘ′は前記の意味を表す］で示される化合物から、一般式Ｆ

[Wherein X ′ represents the above-mentioned meaning]

［式中、Ｒ^１、Ｓｇ、ｐ、ｍ、Ｒ^２は前記の意味を表す］で示される第一エポキシドとの反応により得られる。反応はプロトン性又は非プロトン性溶剤、例えばメタノール、エタノール、ブタノール、プロパノール、ＤＭＦ、トルエン、ＣＨＣｌ_３、ＤＭＡ中で（場合によりその都度水の添加下に）０℃〜１５℃の温度で行われる。幾つかの場合にＬｉＣｌ、ＬｉＢｒ、ＬｉＩ、ＬｉＣｌＯ_４又はＹ（トリフレート）_３のようなルイス酸の添加が有用であることが分かっている。

[Wherein R ¹ , Sg, p, m and R ² represent the above-mentioned meanings] and obtained by reaction with the first epoxide. The reaction is carried out in a protic or aprotic solvent such as methanol, ethanol, butanol, propanol, DMF, toluene, CHCl ₃ , DMA (optionally with addition of water each time) at a temperature between 0 ° C. and 15 ° C. . In some cases it has been found useful to add a Lewis acid such as LiCl, LiBr, LiI, LiClO ₄ or Y (triflate) ₃ .

Compounds of general formula F are available from the literature by known methods (Krawiecka et al., J. Chem. Soc. Perkin Trans. 1, 2001 , 1086) or can be purchased.

The compounds of general formula E are so-called DO3A-derivatives and are described in the literature (Chatal et al., Tetrahedron Lett., 1996 , 7515).

  c) The reaction of the epoxide of general formula VI with the compound of general formula VII is carried out by the method of reaction of epoxides and amines described under b).

  In some cases, the compound

の使用下にEP 0545511に記載された経路を利用することが有利であることが判明している。しかしまたEP 0643705により進められることができるか又はWO 98/55467のもとに記載されたリチウム法が利用されることができる。

It has been found to be advantageous to utilize the route described in EP 0545511 using However, it is also possible to proceed according to EP 0643705 or to use the lithium method described under WO 98/55467.

  The preparation of compound VII in the case of a W′-protecting group, see b) is known from the literature.

Tri-Boc-cyclic compounds are described in Kimura et al., J. Am. Chem. Soc., 1997 , 3068, and tri-Z-cyclic compounds are described in Delaney et al., J. Chem. Soc., Perkin Trans., 1991 , 3329. Yes.

  The compound of general formula VI has the general formula G

で示されるトリオールを一般式Ｈ

The triol represented by general formula H

［ここでｐは前記の意味であり、かつ式中、ＺはＣｌ、Ｂｒ、Ｉ、ＯＴ_ｓを表す］で示されるエポキシドとの反応により入手可能である。

[Wherein p is defined above, and where each, Z is Cl, Br, I, representing the OT _s] is available by reaction of epoxides represented by.

The reaction is carried out by glycid ether formation (p = 1) or etherification methods known from the literature, Mouzin et al., Synthesis, 1983 , 117.

  Compounds of general formula H are known from the literature, for example Sharpless et al., J. Org. Chem., And DE 935433, or are commercially available (eg epichlorohydrin, Fluka, Aldrich).

  Compounds of general formula G when Hal = iodine are described in US 6,310,243. The production of bromine compounds is carried out analogously.

  d) The reaction is carried out by first converting the amide of the compound of general formula IX by methods known to those skilled in the art, for example DMF, THF, DMA, dioxane, NaH in toluene (temperature 0 ° C. to 100 ° C.) or −70 ° to By deprotonation using BuLi, LDA, Li-HMDS, Na-HMDS in THf, MTB at a temperature of 0 ° C., followed by reaction with a compound of general formula VIII (preferred temperature −70-70 ° C.) To be done.

  Compounds of general formula VIII are represented by general formula G

で示される化合物から、当業者に公知の第一ＯＨ−基をハロゲン化物もしくはトシレート、トリフレート等に変換するための方法により得られる。

Is obtained by a method for converting a primary OH group known to those skilled in the art into a halide or tosylate, triflate and the like.

  Compounds of general formula IX are represented by general formula IXa

で示される化合物から、式Ｒ^１ＮＨ_２のアミンとのアミド形成により（前記式のアミドは購入できるかもしくは文献から公知である）、既にａ）のもとで述べられたアミドカップリングの方法により得られる。

The method of amide coupling already described under a) by amide formation with an amine of formula R ¹ NH ₂ from a compound of formula Is obtained.

  Compounds of general formula IXa are described, for example, in WO 97/02051, WO 99/16757 or can be prepared simply from tri-Boc cyclic compounds or tri-Z-cyclic compounds by methods known from the literature .

  The compounds according to the invention can be used in X-ray diagnosis as well as MR diagnosis.

  The high X-ray density associated with their good water solubility of iodinated X-ray contrast agents is combined with the outstanding hydrophilicity of the metal-chelates in the molecule and their inherent good compatibility. The extremely high hydrophilicity of the new compound results in a side effect profile that corresponds to a very well-matched Gd compound as used in MR-imaging. This property therefore makes it particularly suitable for use in patients with allergies detected against iodinated compounds or in cases of atopy present. In particular, the incidence of serious side effects such as bronchospasm and shock or even death is reduced to low levels of MR contrast agents.

  The slight osmolality of the formulation is a general very good compatibility index for new compounds. They are therefore particularly suitable for intravascular (parenteral) applications.

  Depending on the pharmaceutical formulation, contrast agents are exclusively used for X-ray diagnostics (triiodo complexes with diamagnetic metals) but also for X-ray and MRT diagnostics (triiodo complexes with paramagnetic atoms, preferably Gd). be able to. Very advantageously, the compounds can be used, for example, in urography, computed tomography, angiography, gastrographie, mammography, cardiology and neuroradiology. The complexes used are also advantageous in the case of radiation therapy. The compound is suitable for all perfusion measurements. Differentiation between a well-fed region and an ischemic region is possible after intravascular injection. Quite generally these compounds can be used in all indications where conventional contrast agents are used in X-ray diagnosis or MR diagnosis.

  The novel contrast agents are further subject to excitation-transfer-technology (eg Journ. Chem. Phys. 39 (11). 2892 (1963), and WO 03/013616 as long as mobile protons are included in their chemical structure. Reference). This is the case for example with compounds having a hydroxyl group, as described in Example 5 (page 41), Example 6 (page 44), Example 7 (page 47) and Example 8 (page 50). The present application therefore also includes contrast agents which are in principle suitable for this special MRI technique.

  Particularly useful for diagnosis are cerebral infarction and liver tumors or space-occupying processes in the liver and contrasting of abdominal (including kidney) and muscle-skeletal-system tumors. On the basis of the low osmotic pressure, the blood vessels can be visualized particularly advantageously after intraarterial injection but also after intravenous injection.

  If the compound according to the invention is specified for use in MR diagnosis, the metal ion of the signaling group must be paramagnetic. These are in particular the divalent and trivalent ions of the elements with atomic numbers 21-29, 42, 44 and 58-70. Suitable ions are, for example, chromium (III)-, iron (II)-, cobalt (II)-, nickel (II)-, copper (II)-, praseodymium (III)-, neodymium (III)-, samarium ( III)-and ytterbium (III) -ions. Due to their strong magnetic moment, gadolinium (III)-, terbium (III)-, dysprosium (III)-, holmium (III)-, erbium (III)-, iron (III)-and manganese (II)- Ions are preferred, and gadolinium (III)-and manganese (II) -ions are particularly preferred.

  When the compounds according to the invention are designed for use in X-ray diagnostics, the metal ions are preferably derived from higher atomic number elements in order to achieve sufficient absorption of X-rays. For this purpose, it has been found that diagnostic agents containing physiologically compatible complex salts with metal ions of the elements of atomic numbers 25, 26 and 39 and 57-83 have been found suitable.

  Manganese (II)-, iron (II)-, iron (III)-, praseodymium (III)-, neodymium (III)-, samarium (III)-, gadolinium (III)-, ytterbium (III)-or bismuth ( III) -ions, in particular dysprosium (III) ions and yttrium (III) ions, are preferred.

  The preparation of the medicament according to the invention (pharmazeutischen Mittel) is a method known per se, in which the complex compound according to the invention is suspended or dissolved in an aqueous medium, optionally with the usual additives in Galennik. Followed by optionally sterilizing the suspension or solution. Suitable additives are, for example, physiologically harmless buffers (for example tromethamine), complexing agents or weak complexes (for example diethylenetriaminepentaacetic acid or Ca complexes corresponding to the metal complexes according to the invention) or if necessary -An electrolyte, such as sodium chloride or, if necessary, an antioxidant, such as ascorbic acid.

Where suspensions or solutions of the drug according to the invention in water or physiological salt solutions are desired for enteral or parenteral administration or other purposes, these are one or more conventional in Galen Pharmaceuticals. Auxiliaries [eg methylcellulose, lactose, mannitol] and / or surfactants ⁽ eg lecithin, Tween®, Myrj® ⁾ and / or fragrances for taste correction [eg essential oils].

  In principle, the medicament according to the invention can also be produced without isolating the complex. In any case, special care must be taken to perform the chelation so that it is virtually free of toxic metal ions that are not complexed with the complexes according to the invention.

  This can be ensured by control titration during the manufacturing process using a color indicator such as xylenol orange. The invention therefore also relates to a process for the production of complex compounds and their salts. Purification of the complex isolated for final precautions remains.

  Upon in vivo application of the medicaments according to the invention, they can be administered together with a suitable carrier, such as serum or saline and together with other proteins, such as human serum albumin (HSA). .

  The medicament according to the invention is usually applied parenterally, preferably intravenously. These depend on whether the blood vessels / organs should be selectively contrasted (eg visualization of coronary arteries after intraarterial injection) or tissue or pathology (eg diagnosis of brain tumors after intravenous injection). Can also be applied intraarterially or interstitial / intradermally.

  The medicament according to the invention preferably contains 0.001 to 1 mol / l of the compound described above and is usually dosed in an amount of 0.001 to 5 mmol / kg.

The medicament according to the invention fulfills various requirements for its suitability as a contrast agent for magnetic resonance tomography. For example, they are outstandingly suitable for improving in their expressive power the images obtained with an MR tomograph by increasing the signal intensity after oral or parenteral application. Furthermore, they exhibit the high effectiveness required to load the body with as little foreign material as possible and the good suitability required to maintain the non-invasive characteristics of the test. Of great advantage for use in magnetic resonance tomography is the high effectiveness (relaxivity) of the paramagnetic compounds according to the invention. For example, the relaxed state (L / mmol ⁻¹ * sec ⁻¹ ) of a gadolinium-containing compound is typically 2 to 4 times greater than that of a conventional Gd complex (eg, Gadobutrol).

  The good water solubility and low osmolality of the drug according to the invention makes it possible to produce a highly concentrated solution, so that the volumetric load of the circulatory system is maintained within acceptable limits and to compensate for dilution by body fluids. Enable. Furthermore, since the drug according to the invention has not only high stability in vitro, but also surprisingly high stability in vivo, the release or exchange of ions bound in the complex—originally toxic—is It takes place very slowly within the time that the agent is completely excreted again.

  In general, the medicament according to the invention is dosed in an amount of 0.001 to 5 mmol Gd / kg, preferably 0.005 to 0.5 mmol Gd / kg, for use as an MRT diagnostic agent.

  The agents according to the invention are outstandingly suitable as X-ray contrast agents, in which signs of known anaphylactoid reactions are detected in biochemical-pharmacological tests from iodine-containing contrast agents. It can be particularly emphasized that this is not possible. In the case of strong X-ray absorption these are particularly effective within the range of higher tube voltages (eg CT and DSA).

  In general, the medicament according to the invention is dosed for use as an X-ray contrast agent in an amount of 0.01 to 5 mmol / kg, preferably 0.02 to 1 mmol substance / kg, as for example meglumine-diatrizoate. This corresponds, for example, to 0.06-6 mmol (I + Dy) / kg in the case of iodine-Dy compounds.

  Depending on the diagnostic issue, a formulation that can be used in X-ray diagnosis as well as MR diagnosis can be selected. In order to achieve optimal results for both imaging modalities, it may be advantageous to select a formulation with a reduced paramagnetic ion content, since for many uses of MR diagnosis it is paramagnetic. This is because the too high content of ions does not provide another additional benefit.

  For dual use, formulations can be used in which the percentage content of paramagnetic substances (eg Gd) is reduced to 0.05 to 50, preferably 2 to 20%. An example may be the use in cardiology. For the test, the preparation of the substance according to the invention is used at a total concentration of eg 0.25 mol / L. The content of the Gd-containing complex is 20% and the remaining 80% of the metal is for example Dy atoms. In the case of X-ray coronary angiography after intra-arterial or intravenous administration, for example in the case of a patient weighing 50 mL, ie 70 kg, 0.18 mmol substance per kg body weight is used. Immediately after a coronary vessel x-ray is taken, MR diagnosis of the heart is continued so that living myocardial areas can be distinguished from necrotic myocardial areas. An amount of about 110 μmol Gd / kg that is pre-applied for testing is optimal for this.

Examples Example 1
a) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-aminoethyl) amide 10 g (15.5 mmol) of 1,3,5-triiodotrimesic acid trichloride in 100 ml of tetrahydrofuran ) (DE 3001292, Schering AG, priority: 11 January 1980) is added dropwise to 24 g (400 mmol) of ethylenediamine at room temperature over 1 h and stirred after 14 h. The precipitated solid is filtered off, post-washed with ethanol, taken up in 100 ml of water and the resulting solution is adjusted to a pH value of 8.0 using 1M lithium hydroxide solution. Recrystallize from ethanol after evaporation in vacuo.
Yield: 7.8 g of colorless solid (70% of theory)
Elemental analysis:
Calculated value: C 25.23 H 2.96 N 11.77 I 53.31
Found: C 25.46 H 2.99 N 11.68 I 52.98.

b) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3,6-diaza-4,7-dioxo-8-methyloctane-1,8-diyl- {10- [ 1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]}) amide 10- [4-carboxy-1-methyl-2-oxo-3 -Azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid Gd complex 48.5 g (77.09 mmol) (WO 98/24775, Schering AG, Example 1) Is suspended in 400 ml of DMSO, mixed with 9.8 g (84.8 mmol) of N-hydroxysuccinimide and 16.7 g (81 mmol) of dicyclohexylcarbodiimide and preactivated for 1 hour. Subsequently mixed with 12.3 g (17.12 mmol) of 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-aminoethyl) -amide and stirred at room temperature for 3 days under nitrogen. To do. Insoluble components are filtered off and the solution is poured into 2000 ml of acetone. The solid which precipitates at this time is filtered off and washed in portions with 1000 ml of acetone and 500 ml of diethyl ether. The residue is taken up in 500 ml of water, absorbed and precipitated for 2 h with 100 g of ion exchanger (IRA 67 OH-form) and filtered off. It is subsequently adsorbed and precipitated with 30 g of ion exchanger (IR 267 H-form) for 2 h, filtered, mixed with 2 g of activated carbon, warmed to 60 ° C. for 2 hours, filtered and concentrated to 100 ml. In order to remove the remaining dimethyl sulfoxide, the solution is poured into 1000 ml of acetone and the precipitated precipitate is filtered off. The residue is dissolved in 250 ml of water, the conductivity is adjusted to a value of 0.005 mS (pH = 7.0) with a slight ion exchanger (H-form and OH-form), filtered off, Evaporate in vacuum.
Yield: 33.9 g of colorless solid (73% of theory)
Water content (Karl-Fischer): 5.9%
Elemental analysis (for water-free substances):
Calculated value: C 33.92 H 4.15 N 11.54 I 14.93 Gd 18.51
Found: C 33.99 H 4.17 N 11.49 I 14.88 Gd 18.37.

Example 2
1,3,5-triiodotrimesic acid-N, N, N-tris- (3,6-diaza-4,7-dioxooctane-1,8-diyl- {10- [1,4,7 -Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]}) amide 10- [4-carboxy-2-oxo-3-azabutyl] -1,4,7 , 10-tetraazacyclododecane-1,4,7-triacetic acid Gd complex 9.4 g (15.3 mmol) (WO 98/24775, Schering AG, (Example 11)) was suspended in 100 ml of DMSO, Mix with 1.96 g (17 mmol) of N-hydroxysuccinimide and 3.3 g (16 mmol) of dicyclohexylcarbodiimide and pre-activate for 1 hour. Subsequently mixed with 2.4 g (3.36 mmol) of 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-aminoethyl) -amide and stirred at room temperature for 3 days under nitrogen. To do. Insoluble components are filtered off and the solution is poured into 1000 ml of acetone. The solid which precipitates at this time is filtered off and washed little by little with 300 ml of acetone and 100 ml of diethyl ether. The residue is taken up in 200 ml of water, absorbed and precipitated for 2 h with 30 g of ion exchanger (IRA 67 OH-form) and filtered off. Subsequently, it is absorbed and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h, filtered off, mixed with 2 g of activated carbon, warmed to 60 ° C. for 2 hours, filtered off and the solution is concentrated to 100 ml. In order to remove the remaining dimethyl sulfoxide, the solution is poured into 1000 ml of acetone and the precipitated precipitate is filtered off. The residue is dissolved in 250 ml of water, the conductivity is adjusted to a value of 0.005 mS (pH = 7.0) with a slight ion exchanger (H-form and OH-form), filtered off, Evaporate in vacuum.
Yield: 6.0 g of colorless solid (68% of theory)
Water content (Karl-Fischer): 5.4%
Elemental analysis (for water-free substances):
Calculated value: C 33.06 H 3.98 N 11.73 I 15.18 Gd 18.82
Found: C 33.31 H 4.02 N 11.70 I 15.09 Gd 18.74.

Example 3
a) 1,4,7-tris- (benzyloxycarbonyl) -10- (ethoxycarbonylmethyl) -1,4,7,10-tetraazacyclo-dodecane 1,4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecane 68.2 g (118.6 mmol) (Delaney et al., J. Chem. Soc. Perkin Trans. 1991, 3329) was dissolved in 700 ml of acetonitrile and 75. Mix with 4 g (545.5 mmol). Subsequently, 39.6 g (355.5 mmol) of bromoacetic acid ethyl ester are added with vigorous stirring and heated to 40 ° C. for 20 hours. The insoluble components are filtered off, concentrated to dryness and chromatographed on silica gel (eluent ethyl acetate / hexane 20: 1). Fractions containing product are combined and evaporated.
Yield 72.3 g of colorless oil (92% of theory)
Elemental analysis:
Calculated value: C 65.44 H 6.71 N 8.48
Found: C, 65.51 H 6.78 N, 8.43.

b) 1,4,7-tris- (benzyloxycarbonyl) -10- (carboxymethyl) -1,4,7,10-tetraazacyclododecane 1,4,7-tris- (benzyloxycarbonyl) -10 34 g (51.4 mmol) of-(ethoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane are dissolved in 300 ml of dioxane, mixed with 144 ml of 5% aqueous NaOH and stirred at room temperature for 24 h. After neutralization with concentrated HCl, it is concentrated to dryness. The residue is taken up in 250 ml of ethyl acetate and extracted twice with 250 ml each of 1N HCl solution. The organic phase is dried over sodium sulfate and the solvent is concentrated to dryness.
Yield 27.8 g of colorless solid (85% of theory)
Elemental analysis:
Calculated value: C 64.54 H 6.37 N 8.86
Found: C 64.47 H 6.41 N 8.79.

c) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (Benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 1,3,5-triiodotrimesic acid-N, N, N-tris- (2 in 446 ml of DMF -Aminoethyl) amide in a suspension of 16.8 g (23.5 mmol) 1,4,7-tris- (benzyloxycarbonyl) -10- (carboxymethyl) -1,4,7,10-tetraazacyclo 44.6 g (70.6 mmol) of dodecane, 21 ml (164 mmol) of triethylamine, 14.6 g (70.5 mmol) of dicyclohexylcarbodiimide and 8.1 g (70.5 mmol) of N-hydroxysuccinimide were added. Stir at room temperature for 20 h. Insoluble components are filtered off and concentrated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water each time. The organic phase is dried over sodium sulfate, the solvent is concentrated to dryness and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 23.3 g of colorless solid (39% of theory)
Elemental analysis:
Calculated value: C 54.93 H 5.32 N 9.86 I 14.88
Found: C 55.11 H 5.37 N 9.81 I 14.76.

d) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {1- [1,4,7,10- Tetraazacyclododecanyl]})-amide 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [ 1,4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 20 g (7.8 mmol) was carefully added at 0-5 ° C. with HBr / AcOH ( 33%) Mix with 140 ml and stir at room temperature for 3 h. The reaction mixture is subsequently poured into 800 ml of diethyl ether, and the solid that forms is filtered off with suction and washed with diethyl ether several times. The residue is dissolved in 100 ml water and 100 ml dichloromethane and 32% NaOH solution is added with vigorous stirring until a pH value of 10 is reached. The organic phase is separated, the aqueous phase is extracted 3 times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulphate and concentrated to dryness.
Yield 10.3 g of colorless solid (97% of theory)
Elemental analysis:
Calculated value: C 40.01 H 6.04 N 18.66 I 28.18
Found: C 40.19 H 6.07 N 18.60 I 28.11.

e) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (Carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-4- 18.6 g (13.7 mmol) of oxopentane-1,5-diyl- {1- [1,4,7,10-tetraazacyclododecanyl]})-amide was dissolved in 75 ml of water and chloroacetic acid 19 0.5 g (206.5 mmol) is added and adjusted to a pH value of 9.5 with 32% NaOH at 60 ° C. Heat to 70 ° C. for 10 hours, during which time the pH value of the reaction mixture is continuously adjusted to 9.5. After cooling to room temperature, the pH is adjusted to 1 with concentrated HCl and the solution is evaporated in vacuo. The residue is precipitated with 250 ml of methanol, insoluble components are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and added onto an ion exchanger-column (600 ml, IR 120, H ⁺ -form). Subsequently it is washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, and the solid that forms is filtered off with suction, washed several times with diethyl ether and dried in vacuo.
Yield 13.8 g of colorless solid (54% of theory)
Elemental analysis:
Calculated value: C 40.39 H 5.33 N 13.46 I 20.32
Found: C 40.51 H 5.39 N 13.38 I 20.36.

f) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (Carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]}) amide 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza -4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 13 g (6 0.9 mmol) is dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.7 g (10.4 mmol) of gadolinium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined, absorbed and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h, filtered and then absorbed and precipitated with 10 g of ion exchanger (IRA 67 OH-form) for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 6.2 g of colorless solid (36% of theory)
Water content (Karl-Fischer): 6.2%
Elemental analysis (for water-free substances):
Calculated value: C 32.39 H 3.88 N 10.79 I 16.30 Gd 20.20
Found: C 32.44 H 3.89 N 10.71 I 16.33 Gd 20.07.

g) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (Carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Dy complex]}) amide 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza -4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 13 g (6 0.9 mmol) is dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.88 g (10.4 mmol) of dysprosium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined, absorbed and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h, filtered and then absorbed and precipitated with 10 g of ion exchanger (IRA 67 OH-form) for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 7.0 g of colorless solid (41% of theory)
Water content (Karl-Fischer): 5.9%
Elemental analysis (for water-free substances):
Calculated value: C 32.18 H 3.86 N 10.72 I 16.19 Dy 20.73
Found: C 32.32 H 3.91 N 10.67 I 16.11 Dy 20.68.

h) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (Carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Y complex]}) amide 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza -4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 13 g (6 0.9 mmol) is dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.72 g (10.4 mmol) of yttrium carbonate and heat to reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined, absorbed and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h, filtered and then absorbed and precipitated with 10 g of ion exchanger (IRA 67 OH-form) for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 6.5 g of colorless solid (42% of theory)
Water content (Karl-Fischer): 4.8%
Elemental analysis (for water-free substances):
Calculated value: C 35.51 H 4.26 N 11.38 I 17.87 Y 12.52
Found: C 35.73 H 4.31 N 11.31 I 17.79 Y 12.60.

Example 4
a) 1,4,7-tris- (benzyloxycarbonyl) -10- (1-ethoxycarbonylethyl) -1,4,7,10-tetraazacyclo-dodecane 1,4,7-tris- (benzyloxy) Carbonyl) -1,4,7,10-tetraazacyclododecane 50.1 g (87.0 mmol) (Delaney et al., J. Chem. Soc. Perkin Trans. 1991, 3329) was dissolved in 500 ml of acetonitrile and sodium carbonate Mix with 55.5 g (400 mmol). Subsequently, 54.3 g (300 mmol) of 1-bromopropionic acid ethyl ester are added with vigorous stirring and heated to 60 ° C. for 20 hours. The insoluble components are filtered off, concentrated to dryness and chromatographed on silica gel (eluent ethyl acetate / hexane 20: 1). Fractions containing product are combined and evaporated.
Yield 46 g of colorless oil (78% of theory).
Elemental analysis:
Calculated value: C 65.86 H 6.87 N 8.30
Found: C, 65.99 H 6.88 N, 8.23.

b) 1,4,7-tris- (benzyloxycarbonyl) -10- (1-carboxyethyl) -1,4,7,10-tetraazacyclododecane 1,4,7-tris- (benzyloxycarbonyl) -10- (1-Ethoxycarbonylethyl) -1,4,7,10-tetraazacyclododecane (33.7 g, 50 mmol) is dissolved in 300 ml of dioxane, mixed with 140 ml of 5% NaOH aqueous solution, and stirred at room temperature for 24 h. To do. After neutralization with concentrated HCl, it is concentrated to dryness. The residue is taken up in 250 ml of ethyl acetate and extracted twice with 250 ml each of 1N HCl solution. The organic phase is dried over sodium sulfate and the solvent is concentrated to dryness.
Yield 28.2 g of colorless solid (87% of theory)
Elemental analysis:
Calculated value: C 65.00 H 6.55 N 8.66
Found: C 65.22 H 6.59 N 8.60.

c) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-1-methyl-4-oxopentane-1,5-diyl- {10- [1,4, 7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 1,3,5-triiodotrimesic acid in 450 ml DMF-N, N, N- 1,4,7-Tris- (benzyloxycarbonyl) -10- (1-carboxyethyl) -1,4,7 was added to a suspension of 16.8 g (23.5 mmol) of tris- (2-aminoethyl) amide. , 10-tetraazacyclododecane 45.6 g (70.6 mmol), triethylamine 21 ml (164 mmol), dicyclohexylcarbodiimide 14.6 g (70.5 mmol) and N-hydroxysuccinimide 8.1 g (70 5 mmol) is added and 20h stirring at room temperature. Insoluble components are filtered off and concentrated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water each time. The organic phase is dried over sodium sulfate, the solvent is concentrated to dryness and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 24.5 g of colorless solid (40% of theory)
Elemental analysis:
Calculated value: C 55.43 H 5.47 N 9.70 I 14.64
Found: C 55.49 H 5.43 N 9.66 I 14.60.

d) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-1-methyl-4-oxopentane-1,5-diyl- {1- [1,4, 7,10-tetraazacyclododecanyl]})-amide 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 23 g (8.85 mmol) carefully at 0-5 ° C. Mix with 140 ml HBr / AcOH (33%) and stir at room temperature for 3 h. The reaction mixture is subsequently poured into 800 ml of diethyl ether, and the solid that forms is filtered off with suction and washed with diethyl ether several times. The residue is dissolved in 100 ml water and 100 ml dichloromethane and 32% NaOH solution is added with vigorous stirring until a pH value of 10 is reached. The organic phase is separated, the aqueous phase is extracted 3 times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulphate and concentrated to dryness.
Yield 11.7 g of colorless solid (95% of theory)
Elemental analysis:
Calculated value: C 41.39 H 6.29 N 18.10 I 27.33
Found: C, 41.51 H, 6.32 N, 18.01 I, 27.26.

e) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-1-methyl-4-oxopentane-1,5-diyl- {10- [1,4, 7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 1,3,5-triiodotrimesic acid-N, N, N-tris- (3- Aza-1-methyl-4-oxopentane-1,5-diyl- {1- [1,4,7,10-tetraazacyclododecanyl]})-amide 18.8 g (13.5 mmol) is added to 75 ml of water. Dissolve in, add 19.5 g (206.5 mmol) of chloroacetic acid and adjust to a pH value of 9.5 with 32% NaOH at 60 ° C. Heat to 70 ° C. for 10 hours, during which time the pH value of the reaction mixture is continuously adjusted to 9.5. After cooling to room temperature, the pH is adjusted to 1 with concentrated HCl and the solution is evaporated in vacuo. The residue is precipitated with 250 ml of methanol, insoluble components are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and added onto an ion exchanger-column (600 ml, IR 120, H ⁺ -form). Subsequently it is washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, and the solid that forms is filtered off with suction, washed several times with diethyl ether and dried in vacuo.
Yield 15.0 g of colorless solid (58% of theory)
Elemental analysis:
Calculated value: C 41.39 H 5.53 N 13.16 I 19.88
Found: C 41.46 H 5.537 N 13.11 I 19.79.

f) 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-aza-1-methyl-4-oxopentane-1,5-diyl- {10- [1,4, 7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]}) amide 2,4,6-triiodotrimesic acid-N, N, N-tris- (3-Aza-1-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl ]})-Amid 13.2 g (6.9 mmol) is dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.7 g (10.4 mmol) of gadolinium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined, absorbed and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h, filtered and then absorbed and precipitated with 10 g of ion exchanger (IRA 67 OH-form) for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 7.1 g of colorless solid (41% of theory)
Water content (Karl-Fischer): 5.6%
Elemental analysis (for water-free substances):
Calculated value: C 33.34 H 4.07 N 10.60 I 16.01 Gd 19.84
Found: C 33.51 H 4.14 N 10.53 I 15.98 Gd 19.76.

Example 5
a) Dibenzyloxiranylmethylamine 98.6 g (0.5 mol) of dibenzylamine and 55.5 g (0.6 mol) of epichlorohydrin are dissolved in 500 ml of methanol and heated to 80 ° C. for 6 hours. The solution is evaporated to dryness and mixed with 500 ml of t-butanol. While stirring, a solution of 36.4 g (0.65 mol) of potassium hydroxide in 50 ml of water is now added and heated to 80 ° C. for 2 hours. After cooling to room temperature, the potassium chloride formed is filtered off and the filtrate is concentrated to dryness and chromatographed on silica gel (eluent hexane / ethyl acetate 10: 1). Fractions containing product are combined and evaporated.
Yield 126 g of colorless oil (99% of theory)
Elemental analysis:
Calculated value: C 80.60 H 7.56 N 5.53
Found: C 80.72 H 7.59 N 5.51.

b) [1- (3-Dibenzylamino-2-hydroxypropyl) -1,4,7,10-tetraazacyclododecane] pentahydrochloride 1,4,7,10-tetra dissolved in 700 ml of toluene To 100 g (5800.48 mmol) of azacyclododecane is added 100 ml (752.77 mmol) of N, N-dimethylformamide dimethylacetal and heated to 120 ° C. for 2 h under nitrogen. At that time, the methanol / toluene-azeotrope is continuously distilled off. The reaction mixture is subsequently concentrated in vacuo at 70 ° C., 157 g (620 mmol) of dibenzyloxiranylmethylamine are added and heated to 110 ° C. under nitrogen for 24 h. After cooling to room temperature, it is mixed with 500 ml of water and extracted twice with 200 ml of ethyl acetate each time. The aqueous phase is mixed with 250 ml of concentrated HCl and subsequently heated to 80 ° C. for 12 hours. Evaporate to dryness, mix with 200 ml of ethanol and 200 ml of methanol and evaporate again to dryness. The residue is dissolved hot in 600 ml of ethanol and subsequently slowly cooled to 0 ° C., during which a white solid crystallizes out. The solid is filtered off, washed with ethanol and subsequently dried in vacuo at 50 ° C.
Yield: 280 g of colorless solid (79% of theory)
Elemental analysis:
Calculated value: C 49.39 H 7.29 N 11.52 Cl 29.16
Found: C 49.67 H 7.44 N 11.56 Cl 28.22.

c) 10- (3-Dibenzylamino-2-hydroxypropyl) -1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane 500 ml water and 500 ml dichloromethane While stirring vigorously in 250 g (411.2 mmol) of [1- (3-dibenzylamino-2-hydroxypropyl) -1,4,7,10-tetraazacyclododecane] pentahydrochloride dissolved in 32% NaOH solution is added until a pH value of is reached. The organic phase is separated, the aqueous phase is extracted three times with 250 ml each of dichloromethane, and the combined organic phases are dried over magnesium sulfate and concentrated to dryness. The residue is dissolved in 1200 ml of acetonitrile and mixed with 176.2 g (1.275 mol) of potassium carbonate. Subsequently, 248.7 g (1.275 mol) of bromoacetic acid-t-butyl ester are added with vigorous stirring and heated to 60 ° C. for 3 hours. The insoluble components are filtered off, concentrated to dryness and chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 262 g of colorless solid (83% of theory)
Elemental analysis:
Calculated value: C 67.25 H 9.05 N 9.12.
Found: C 67.33 H 9.02 N 9.15.

d) 10- (3-amino-2-hydroxypropyl) -1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane 10- (3-dibenzyl) Amino-2-hydroxypropyl) -1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane 76.8 g (100 mmol) was dissolved in 500 ml of methanol, Mix with 40 ml water and add 10 g palladium catalyst (20% Pd / C). Hydrogenate at 50 ° C. under normal pressure for 8 hours. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.
Yield: 58.5 g of colorless powder (quantitative)
Elemental analysis:
Calculated value: C 59.26 H 9.77 N 11.91
Found: C 59.48 H 9.86 N 11.67.

e) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris- (t-butoxy) Carbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide 12.86 g (20 mmol) of 1,3,5-triiodotrimesic acid trischloride dissolved in 400 ml of tetrahydrofuran (DE 3001292 Schering AG, priority: 11 January 1980) and 12.2 g (120 mmol) of triethylamine followed by 10- (3-amino-2-hydroxypropyl) -1,4,7-tris- (t-butoxy Add 38.8 g (66 mmol) of carbonylmethyl) -1,4,7,10-tetraazacyclododecane and stir at room temperature for 6 h. The insoluble components are filtered off, concentrated to dryness and chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 32.7 g of colorless solid (71% of theory)
Elemental analysis:
Calculated value: C 50.19 H 7.37 N 9.15 I 16.57
Found: C, 50.33 H, 7.40 N, 9.11, and 16.43.

f) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide 34.5 g (15 mmol) was dissolved in 100 ml of dichloromethane. Mix with 100 ml of trifluoroacetic acid at 0 ° C. and stir at 0 ° C. for 3 hours. The batch is poured into 500 ml of diethyl ether, the precipitated solid is filtered off, washed with 3 × 100 ml of diethyl ether and dried in vacuo.
Yield 25.3 g of colorless solid (94% of theory)
Elemental analysis:
Calculated value: C 40.21 H 5.40 N 11.72 I 21.24
Found: C 40.44 H 5.49 N 11.67 I 21.11.

g) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris- (carboxylatomethyl) ) -1,4,7,10-tetraazacyclododecanyl]}, Gd complex) amide 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1, 2-Diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide 21.5 g (12 mmol) dissolved in 250 ml of water And acidified by addition of 5 ml acetic acid. Add 13 g (36.2 mmol) of gadolinium oxide and heat at reflux for 3 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 20/20/1). Fractions containing the product are combined, absorbed and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h, filtered and then absorbed and precipitated with 10 g of ion exchanger (IRA 67 OH-form) for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield: 19.4 g of colorless solid (68% of theory)
Water content (Karl-Fischer): 5.3%
Elemental analysis (for water-free substances):
Calculated value: C 31.96 H 3.89 N 9.32 I 16.88 Gd 20.92
Found: C 32.11 H 3.94 N 9.28 I 16.77 Gd 20.79.

Example 6
a) 1-Benzyl-1-methyl (oxiranylmethyl) amine 60.6 g (0.5 mol) of benzylmethylamine and 55.5 g (0.6 mol) of epichlorohydrin are dissolved in 500 ml of methanol, and the reaction time is 6 hours. Heat to 80 ° C. The solution is evaporated to dryness and mixed with 500 ml of t-butanol. While stirring, a solution of 36.4 g (0.65 mol) of potassium hydroxide in 50 ml of water is now added and heated to 80 ° C. for 2 hours. After cooling to room temperature, the potassium chloride formed is filtered off and the filtrate is concentrated to dryness and chromatographed on silica gel (eluent hexane / ethyl acetate 10: 1). Fractions containing product are combined and evaporated.
Yield 85 g of colorless oil (96% of theory)
Elemental analysis:
Calculated value: C 74.54 H 8.53 N 7.90
Found: C 74.68 H 8.55 N 7.82.

b) [1- (3-Benzylmethylamino-2-hydroxypropyl) -1,4,7,10-tetraazacyclododecane] pentahydrochloride 1,4,7,10-tetra dissolved in 700 ml of toluene To 100 g (5800.48 mmol) of azacyclododecane is added 100 ml (752.77 mmol) of N, N-dimethylformamide dimethylacetal and heated to 120 ° C. for 2 h under nitrogen. At that time, the methanol / toluene-azeotrope is continuously distilled off. The reaction mixture is subsequently concentrated in vacuo at 70 ° C., 110 g (620 mmol) of 1-benzyl-1-methyl (oxiranylmethyl) amine are added and heated to 110 ° C. under nitrogen for 24 h. After cooling to room temperature, it is mixed with 500 ml of water and extracted twice with 200 ml of ethyl acetate each time. The aqueous phase is mixed with 250 ml of concentrated HCl and subsequently heated to 80 ° C. for 12 hours. Evaporate to dryness, mix with 200 ml of ethanol and 200 ml of methanol and evaporate again to dryness. The residue is dissolved hot in 600 ml of ethanol and subsequently slowly cooled to 0 ° C., when a white solid crystallizes out. The solid is filtered off, washed with ethanol and subsequently dried in vacuo at 50 ° C.
Yield: 235 g of colorless solid (76% of theory)
Elemental analysis:
Calculated value: C 42.91 H 7.58 N 13.17 Cl 33.33
Found: C 43.34 H 7.60 N 13.29 Cl 32.78.

c) 10- (3-Benzylmethylamino-2-hydroxypropyl) -1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane 500 ml water and 500 ml dichloromethane While stirring vigorously in 212.7 g (400 mmol) of [1- (3-benzylmethylamino-2-hydroxypropyl) -1,4,7,10-tetraazacyclododecane] pentahydrochloride dissolved in 10 32% NaOH solution is added until a pH value of is reached. The organic phase is separated, the aqueous phase is extracted three times with 250 ml each of dichloromethane, and the combined organic phases are dried over magnesium sulfate and concentrated to dryness. The residue is dissolved in 1200 ml of acetonitrile and mixed with 176.2 g (1.275 mol) of potassium carbonate. Subsequently, 248.7 g (1.275 mol) of bromoacetic acid-t-butyl ester are added with vigorous stirring and heated to 60 ° C. for 3 hours. The insoluble components are filtered off, concentrated to dryness and chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 219 g of colorless solid (79% of theory)
Elemental analysis:
Calculated value: C 64.23 H 9.47 N 10.12
Found: C 64.38 H 9.50 N 10.07.

d) 10- (3-Methylamino-2-hydroxypropyl) -1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane 10- (3-benzyl 69.2 g (100 mmol) of methylamino-2-hydroxypropyl) -1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane was dissolved in 500 ml of methanol. Mix with 40 ml of water and add 10 g of palladium catalyst (20% Pd / C). Hydrogenate at 50 ° C. under normal pressure for 8 hours. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.
Yield: 60 g of colorless powder (quantitative)
Elemental analysis:
Calculated value: C 59.67 H 9.88 N 11.64
Found: C 59.89 H 9.81 N 11.52.

e) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris- (t-butoxy) Carbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) methylamide 12.86 g (20 mmol) of 1,3,5-triiodotrimesic acid trischloride dissolved in 400 ml of tetrahydrofuran (DE 3001292 Schering AG, priority: 11 January 1980), 12.2 g (120 mmol) of triethylamine and subsequently 10- (3-methylamino-2-hydroxypropyl) -1,4,7-tris- (t- Butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane (39.7 g, 66 mmol) is added and stirred at room temperature for 18 h. The insoluble components are filtered off, concentrated to dryness and chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 31.4 g of colorless solid (67% of theory)
Elemental analysis:
Calculated value: C 50.83 H 7.50 N 8.98 I 16.41
Found: C 50.99 H 7.57 N 8.90 I 16.22.

f) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) methylamide 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) 35.1 g (15 mmol) of methylamide was dissolved in 100 ml of dichloromethane. Mix with 100 ml of trifluoroacetic acid at 0 ° C. and stir at 0 ° C. for 3 hours. The batch is poured into 500 ml of diethyl ether, the precipitated solid is filtered off, washed with 3 × 100 ml of diethyl ether and dried in vacuo.
Yield 26.4 g of colorless solid (96% of theory)
Elemental analysis:
Calculated value: C 40.25 H 5.60 N 11.45 I 20.75
Found: C 40.17 H 5.69 N 11.51 I 20.58.

g) 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1,3-diyl- {10- [1,4,7-tris- (carboxylatomethyl) ) -1,4,7,10-tetraazacyclododecanyl]}, Gd complex) methylamide 1,3,5-triiodotrimesic acid-N, N, N-tris- (2-hydroxypropane-1, 3-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) methylamide 22 g (12 mmol) is dissolved in 250 ml of water, Acidify by adding 5 ml of acetic acid. Add 13 g (36.2 mmol) of gadolinium oxide and heat at reflux for 3 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 20/20/1). Fractions containing the product are combined, absorbed and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h, filtered and then absorbed and precipitated with 10 g of ion exchanger (IRA 67 OH-form) for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield: 18.2 g of colorless solid (62% of theory)
Water content (Karl-Fischer): 6.1%
Elemental analysis (for water-free substances):
Calculated value: C 32.94 H 4.08 N 9.15 I 16.57 Gd 20.54
Found: C 33.21 H 4.13 N 9.10 I 16.43 Gd 20.22.

Example 7
a) 1,3,5-triiodo-2,4,6-tris- (oxiranylmethoxymethyl) benzene 11.0 g of 1,3,5-triiodo-2,4,6-trishydroxymethylbenzene (20. 1 mmol), 55.5 g (0.6 mol) of epichlorohydrin and 1.1 g (3.2 mmol) of tetrabutylammonium hydrogen sulfate, 55 ml of 32% NaOH solution are added dropwise at room temperature over 1 h, followed by Stir for 12 h. Mix with 150 ml of water and extract twice with 200 ml of toluene each time. The combined organic phases are dried over sodium sulfate, the solvent is concentrated to dryness and chromatographed on silica gel (eluent hexane / ethyl acetate 10: 1). Fractions containing product are combined and evaporated.
Yield 10.5 g of colorless solid (73% of theory)
Elemental analysis:
Calculated value: C 30.28 H 2.96 I 53.32.
Found: C 30.44 H 2.99 I 53.21.

b) 1,3,5-triiodo- {2,4,6-tris [2-hydroxy-3- (1,4,7,10-tetraazacyclododecan-1-yl) propyloxy-methyl]} benzene To 10 g (58.05 mmol) of 1,4,7,10-tetraazacyclododecane dissolved in 100 ml of toluene was added 10 ml (75.28 mmol) of N, N-dimethylformamide dimethylacetal, and the mixture was heated to 120 ° C. under nitrogen. Heat for 2 h. At that time, the methanol / toluene-azeotrope is continuously distilled off. The reaction mixture is subsequently concentrated in vacuo at 70 ° C., 13.6 g (19.1 mmol) of 1,3,5-triiodo-2,4,6-tris- (oxiranylmethoxymethyl) benzene are added, Heat to 110 ° C. under nitrogen for 24 h. After cooling to room temperature, it is mixed with 100 ml of 2N HCl and subsequently heated to 80 ° C. for 12 hours. Evaporate to dryness, mix with 50 ml of ethanol and 50 ml of methanol and evaporate again to dryness. The residue is dissolved hot in 100 ml of ethanol and subsequently slowly cooled to 0 ° C., during which a white solid crystallizes out. The solid is filtered off, washed with ethanol and subsequently dried in vacuo at 50 ° C. The solid is dissolved in 100 ml of water and 100 ml of dichloromethane and 32% NaOH solution is added with vigorous stirring until a pH value of 10 is reached. The organic phase is separated, the aqueous phase is extracted 3 times with 100 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulphate and concentrated to dryness.
Yield: 19.0 g of colorless solid (81% of theory)
Elemental analysis:
Calculated value: C 40.98 H 6.63 N 13.66 I 30.93
Found: C 41.32 H 6.71 N 13.54 I 30.77.

c) 1,3,5-triiodo- {2,4,6-tris [2-hydroxy-3- (1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane-1) -Yl) propyloxymethyl]} benzene 1,3,5-triiodo- {2,4,6-tris [2-hydroxy-3- (1,4,7,10-tetraazacyclododecan-1-yl) 16.6 g (13.5 mmol) of propyloxy-methyl]} benzene are dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid are added and 9.5 with 32% NaOH at 60 ° C. Adjust to pH value. Heat to 70 ° C. for 10 hours, during which time the pH value of the reaction mixture is continuously adjusted to 9.5. After cooling to room temperature, the pH is adjusted to 1 with concentrated HCl and the solution is evaporated in vacuo. The residue is precipitated with 250 ml of methanol, insoluble components are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and added onto an ion exchanger-column (600 ml, IR 120, H ⁺ -form). Subsequently it is washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, and the solid that forms is filtered off with suction, washed several times with diethyl ether and dried in vacuo.
Yield 14.4 g of colorless solid (61% of theory)
Elemental analysis:
Calculated value: C 41.11 H 5.69 N 9.59 I 21.71
Found: C 41.34 H 5.56 N 9.62 I 21.45.

d) 1,3,5-triiodo- {2,4,6-tris [2-hydroxy-3- (1,4,7-triscarboxylatomethyl-1,4,7,10-tetraazacyclododecane- 1-yl) propyloxymethyl] Gd complex} benzene 1,3,5-triiodo- {2,4,6-tris [2-hydroxy-3- (1,4,7-triscarboxymethyl-1,4, 7,10-tetraazacyclododecan-1-yl) propyloxymethyl]} benzene 12.1 g (6.9 mmol) is dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.7 g (10.4 mmol) of gadolinium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined, absorbed and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h, filtered and then absorbed and precipitated with 10 g of ion exchanger (IRA 67 OH-form) for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 7.0 g of colorless solid (43% of theory)
Water content (Karl-Fischer): 5.4%
Elemental analysis (for water-free substances):
Calculated value: C 32.52 H 4.09 N 7.59 I 17.18 Gd 21.29
Found: C 32.88 H 4.19 N 7.62 I 17.00 Gd 20.99.

Example 8
a) 10- [4-Aza-6- (benzyloxycarbonylamino) -5-oxo-2-hydroxyhexyl] -1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7, 21.97 g (105 mmol) of 10-tetraazacyclododecane Z-glycine was dissolved in 400 ml of DMF and mixed with 12.1 g (105 mmol) of N-hydroxysuccinimide and 21.7 g (105 mmol) of dicyclohexylcarbodiimide under ice cooling. Pre-activate in ice for 1 hour. Subsequently 58.8 g (100 mmol) of 10- (3-amino-2-hydroxypropyl) -1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane and Add 15.4 ml (120 mmol) of triethylamine and stir overnight at room temperature. Insoluble components are filtered off and concentrated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water each time. The organic phase is dried over sodium sulfate, the solvent is concentrated to dryness and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield: 63.2 g of colorless solid (81% of theory)
Elemental analysis:
Calculated value: C 60.13 H 8.54 N 10.79
Found: C 60.32 H 8.561 N 10.59.

b) 10- (4-Aza-6-amino-5-oxo-2-hydroxyhexyl) -1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclo Dodecane 10- [4-aza-6- (benzyloxycarbonylamino) -5-oxo-2-hydroxyhexyl] -1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10 -60 g (77 mmol) of tetraazacyclododecane are dissolved in 500 ml of methanol, mixed with 40 ml of water and 10 g of palladium catalyst (10% Pd / C) are added. Hydrogenate at 50 ° C. under normal pressure for 8 hours. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.
Yield: 48.8 g of colorless solid (98% of theory)
Elemental analysis:
Calculated value: C 57.74 H 9.38 N 13.03
Found: C 57.68 H 9.44 N 13.11.

c) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-2-oxo-5-hydroxyhexane-1,6-diyl- {10- [1,4, 7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide 1,3,5-triiodotrimesic acid triscurolide 12 dissolved in 400 ml of tetrahydrofuran 86 g (20 mmol) (DE 3001292, Schering AG, priority: 11 January 1980) to 12.2 g (120 mmol) triethylamine and subsequently 10- (4-aza-6-amino-5-oxo-2- Add 42.6 g (66 mmol) of hydroxyhexyl) -1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane and stir at room temperature for 6 h. The insoluble components are filtered off, concentrated to dryness and chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 36.5 g of colorless solid (74% of theory)
Elemental analysis:
Calculated value: C 49.63 H 7.23 N 10.21 I 15.42
Found: C 49.97 H 7.31 N 10.12 I 15.26.

d) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-2-oxo-5-hydroxyhexane-1,6-diyl- {10- [1,4, 7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza -2-oxo-5-hydroxyhexane-1,6-diyl- {10- (1,4,7-tris- (t-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl] }) 34.6 g (14 mmol) of the amide is dissolved in 100 ml of dichloromethane, mixed with 100 ml of trifluoroacetic acid at 0 ° C. and stirred for 3 hours at 0 ° C. The batch is poured into 500 ml of diethyl ether and the precipitated solid is filtered off. Separate and di Chirueteru washed after 3 times with each 100 ml, dried in vacuo.
Yield 26.0 g of colorless solid (95% of theory)
Elemental analysis:
Calculated value: C 40.38 H 5.39 N 12.84 I 19.39
Found: C, 40.56 H, 5.45 N, 12.78 I, 19.17.

e) 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-aza-2-oxo-5-hydroxyhexane-1,6-diyl- {10- [1,4, 7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl]}, Gd complex) amide 1,3,5-triiodotrimesic acid-N, N, N-tris- (3-Aza-2-oxo-5-hydroxyhexane-1,6-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl ]}) 23.6 g (12 mmol) of amide are dissolved in 250 ml of water and acidified by addition of 5 ml of acetic acid. Add 13 g (36.2 mmol) of gadolinium oxide and heat at reflux for 3 h. After complexation is completed, the pH is again adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 20/20/1). Fractions containing the product are combined, absorbed and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h, filtered and then absorbed and precipitated with 10 g of ion exchanger (IRA 67 OH-form) for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield: 20.8 g of colorless solid (67% of theory)
Water content (Karl-Fischer): 6.4%
Elemental analysis (for water-free substances):
Calculated value: C 32.68 H 3.99 N 10.39 I 15.69 Gd 19.45
Found: C 32.99 H 4.07 N 10.35 I 15.53 Gd 19.22.

Example 9
a) 1,3,5-triiodo-2,4,6-tris- (toluenesulfonyloxy) methylbenzene 32% NaOH solution 200 ml and toluene 300 ml 1,3,5-triiodo-2,4,6- To a mixture consisting of 50.0 g (91.4 mmol) of trishydroxymethylbenzene and 3 g (8.7 mmol) of tetrabutylammonium hydrogen sulfate is added dropwise 76.3 g (400 mmol) of toluenesulfonic acid chloride at room temperature, followed by stirring for 12 h. . Mix with 300 ml of water and extract twice with 200 ml of toluene. The combined organic phases are dried over sodium sulfate, the solvent is concentrated to dryness and chromatographed on silica gel (eluent hexane / ethyl acetate 10: 1). Fractions containing product are combined and evaporated.
Yield 47.2 g of colorless solid (51% of theory)
Elemental analysis:
Calculated value: C 35.73 H 2.70 I 37.75
Found: C 36.03 H 2.77 I 37.56.

b) 1,4,7-tris- (benzyloxycarbonyl) -10- (carbamidomethyl) -1,4,7,10-tetraazacyclododecane 1,4,7-tris- (benzyloxy) in 500 ml of THF Isobutyl chloroformate in a solution of 75 g (118.7 mmol) of carbonyl) -10- (carboxymethyl) -1,4,7,10-tetraazacyclododecane and 16.9 g (130.5 mmol) of diisopropylethylamine at −20 ° C. 17.8 g (130.5 mmol) are added dropwise. The mixture is subsequently stirred at −20 ° C. for 1 hour and carefully mixed with 20 ml of 25% aqueous ammonia. After stirring for 2 h at 0 ° C., the solvent is subsequently distilled off in vacuo and the residue is chromatographed on silica gel (eluent ethyl acetate / hexane 10: 1). Fractions containing product are combined and evaporated.
Yield 60.7 g of colorless solid (81% of theory)
Elemental analysis:
Calculated value: C 64.64 H 6.54 N 11.09
Found: C 64.81 H 6.549 N 11.00.

c) 1,3,5-triiodo-2,4,6-tris- (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene 1,4,7-tris- (benzyloxycarbonyl) -10- (carbamidomethyl) -1,4,7,10-tetraazacyclo 44.6 g (70.6 mmol) of dodecane are dissolved in 500 ml of THF, mixed with 1.71 g (71 mmol) of sodium hydride under argon at 0 ° C. and stirred for 1 h at room temperature. Subsequently, a solution of 20.2 g (20 mmol) of 1,3,5-triiodo-2,4,6-tris- (toluenesulfonyloxy) methylbenzene in 150 ml of THF is added dropwise and stirred at reflux for 20 h. After cooling, the insoluble components are filtered off and concentrated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water each time. The organic phase is dried over sodium sulfate, the solvent is concentrated to dryness and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 29.4 g of colorless solid (62% of theory)
Elemental analysis:
Calculated value: C 55.85 H 5.32 N 8.80 I 15.95
Found: C, 56.07 H 5.39 N 8.67 I 15.76.

d) 1,3,5-triiodo-2,4,6-tris- {2-aza-3-oxobutane-1,4-diyl- [10- (1,4,7,10-tetraazacyclododecanyl) )]} Benzene 1,3,5-triiodo-2,4,6-tris- (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris- (benzyloxy) Carbonyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene (20 g, 8.4 mmol) was carefully mixed with 140 ml HBr / AcOH (33%) at 0-5 ° C. and stirred at room temperature for 3 h. To do. The reaction mixture is subsequently poured into 800 ml of diethyl ether, and the solid that forms is filtered off with suction and washed with diethyl ether several times. The residue is dissolved in 100 ml water and 100 ml dichloromethane and 32% NaOH solution is added with vigorous stirring until a pH value of 10 is reached. The organic phase is separated, the aqueous phase is extracted 3 times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulphate and concentrated to dryness.
Yield 9.1 g of colorless solid (91% of theory)
Elemental analysis:
Calculated value: C 39.70 H 6.15 N 17.81 I 32.27
Found: C 39.91 H 6.22 N 17.75 I 32.09.

e) 1,3,5-triiodo-2,4,6-tris- (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris- (carboxymethyl)- 1,4,7,10-tetraazacyclododecanyl]}) benzene 1,3,5-triiodo-2,4,6-tris- {2-aza-3-oxobutane-1,4-diyl- [10 -(1,4,7,10-tetraazacyclododecanyl)]} benzene (17.7 g, 15 mmol) was dissolved in water (75 ml), chloroacetic acid (19.5 g, 206.5 mmol) was added, and Adjust to a pH value of 9.5 using 32% NaOH. Heat to 70 ° C. for 10 hours, during which time the pH value of the reaction mixture is continuously adjusted to 9.5. After cooling to room temperature, the pH is adjusted to 1 with concentrated HCl and the solution is evaporated in vacuo. The residue is precipitated with 250 ml of methanol, insoluble components are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and added onto an ion exchanger-column (600 ml, IR 120, H ⁺ -form). Subsequently it is washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, and the solid formed in this case is filtered off with suction, washed several times with diethyl ether and dried in vacuo.
Yield 13.8 g of colorless solid (54% of theory)
Elemental analysis:
Calculated value: C 40.22 H 5.33 N 12.34 I 22.37
Found: C 40.43 H 5.37 N 12.25 I 22.19.

f) 1,3,5-triiodo-2,4,6-tris- (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl]}, Gd complex) benzene 1,3,5-triiodo-2,4,6-tris- (2-aza-3-oxobutane-1,4- Diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) 11.7 g (6.9 mmol) of benzene dissolved in 100 ml of water And acidified by addition of 3 ml acetic acid. Add 3.7 g (10.4 mmol) of gadolinium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined, absorbed and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h, filtered and then absorbed and precipitated with 10 g of ion exchanger (IRA 67 OH-form) for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 8.4 g of colorless solid (53% of theory)
Water content (Karl-Fischer): 6.1%
Elemental analysis (for water-free substances):
Calculated value: C 31.63 H 3.77 N 9.71 I 17.59 Gd 21.79
Found: C 31.77 H 3.72 N 9.76 I 17.45 Gd 21.63.

g) 1,3,5-triiodo-2,4,6-tris- (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl]}, Dy complex) benzene 1,3,5-triiodo- {2,4,6-tris- [2- (4,7,10-triscarboxy) 11.7 g (6.9 mmol) of methyl-1,4,7,10-tetraazacyclododecan-1-ylacetylamino) methyl]} benzene are dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.88 g (10.4 mmol) of dysprosium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h with stirring, filtered and then precipitated with 10 g of ion exchanger (IRA 67 OH-form) with stirring for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 7.5g of colorless solid (47% of theory)
Water content (Karl-Fischer): 5.9%
Elemental analysis (for water-free substances):
Calculated value: C 31.40 H 3.74 N 9.64 I 17.46 Dy 22.36
Found: C, 31.65 H 3.79 N 9.67 I 17.25 Dy 22.11.

h) 1,3,5-triiodo-2,4,6-tris- (2-aza-3-oxobutane-1,4-diyl- {10- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl]}, Y complex) benzene 1,3,5-triiodo- {2,4,6-tris- [2- (4,7,10-triscarboxy) 11.7 g (6.9 mmol) of methyl-1,4,7,10-tetraazacyclododecan-1-ylacetylamino) methyl]} benzene are dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.72 g (10.4 mmol) of yttrium carbonate and heat to reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h with stirring, filtered and then precipitated with 10 g of ion exchanger (IRA 67 OH-form) with stirring for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 8.7 g of colorless solid (61% of theory)
Water content (Karl-Fischer): 5.4%
Elemental analysis (for water-free substances):
Calculated value: C 34.93 H 4.17 N 10.72 I 19.43 Y 13.61
Found: C 35.12 H 4.11 N 10.79 I 19.34 Y 13.52.

Example 10
a) 1,4,7-Tris- (benzyloxycarbonyl) -10- (1-carbamidoethyl) -1,4,7,10-tetraazacyclododecane 1,4,7-Tris- (500 ml in THF) Benzyloxycarbonyl) -10- (1-carboxyethyl) -1,4,7,10-tetraazacyclododecane 76.8 g (118.7 mmol) and diisopropylethylamine 16.9 g (130.5 mmol) in a solution of −20 17.8 g (130.5 mmol) of isobutyl chloroformate are added dropwise at 0 ° C. The mixture is subsequently stirred at −20 ° C. for 1 hour and carefully mixed with 20 ml of 25% aqueous ammonia. After stirring for 2 h at 0 ° C., the solvent is subsequently distilled off in vacuo and the residue is chromatographed on silica gel (eluent ethyl acetate / hexane 10: 1). Fractions containing product are combined and evaporated.
Yield 59.8 g of colorless solid (78% of theory)
Elemental analysis:
Calculated value: C 65.10 H 6.71 N 10.85
Found: C 65.34 H 6.86 N 10.67.

b) 1,3,5-triiodo-2,4,6-tris- (2-aza-4-methyl-3-oxobutane-1,4-diyl- {10- [1,4,7-tris- ( Benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene 1,4,7-tris- (benzyloxycarbonyl) -10- (1-carbamidoethyl) -1,4,7 , 10-tetraazacyclododecane (45.6 g, 70.6 mmol) is dissolved in 500 ml of THF, mixed with 1.71 g (71 mmol) of sodium hydride under argon at 0 ° C. and stirred for 1 h at room temperature. Subsequently, a solution of 20.2 g (20 mmol) of 1,3,5-triiodo-2,4,6-tris- (toluenesulfonyloxy) methylbenzene in 150 ml of THF is added dropwise and stirred at reflux for 20 h. After cooling, the insoluble components are filtered off and concentrated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water each time. The organic phase is dried over sodium sulfate, the solvent is concentrated to dryness and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 27.7 g of colorless solid (57% of theory)
Elemental analysis:
Calculated value: C 56.37 H 5.48 N 8.65 I 15.67
Found: C, 56.56 H, 5.39 N, 8.73 I, 15.46.

c) 1,3,5-triiodo-2,4,6-tris- {2-aza-4-methyl-3-oxobutane-1,4-diyl- [10- (1,4,7,10-tetra Azacyclododecanyl)]} benzene 1,3,5-triiodo-2,4,6-tris- (2-aza-4-methyl-3-oxobutane-1,4-diyl- {10- [1,4 , 7-Tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]}) 25 g (10.3 mmol) of benzene at 0-5 ° C. carefully with HBr / AcOH (33%) 150 ml And stirred at room temperature for 3 h. The reaction mixture is subsequently poured into 800 ml of diethyl ether, and the solid that forms is filtered off with suction and washed with diethyl ether several times. The residue is dissolved in 100 ml water and 100 ml dichloromethane and 32% NaOH solution is added with vigorous stirring until a pH value of 10 is reached. The organic phase is separated, the aqueous phase is extracted 3 times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulphate and concentrated to dryness.
Yield 11.4 g of colorless solid (90% of theory)
Elemental analysis:
Calculated value: C 41.29 H 6.43 N 17.19 I 31.16
Found: C 41.44 H 6.49 N 17.07 I 31.00.

d) 1,3,5-triiodo-2,4,6-tris- (2-aza-4-methyl-3-oxobutane-1,4-diyl- {10- [1,4,7-tris- ( Carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene 1,3,5-triiodo-2,4,6-tris- {2-aza-4-methyl-3-oxobutane- 18.3 g (15 mmol) of 1,4-diyl- [10- (1,4,7,10-tetraazacyclododecanyl)]} benzene was dissolved in 75 ml of water and 19.5 g (206.5 mmol) of chloroacetic acid. ) And adjust to a pH value of 9.5 with 32% NaOH at 60 ° C. Heat to 70 ° C. for 10 hours, during which time the pH value of the reaction mixture is continuously adjusted to 9.5. After cooling to room temperature, the pH is adjusted to 1 with concentrated HCl and the solution is evaporated in vacuo. The residue is stirred and precipitated with 250 ml of methanol, insoluble components are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and added onto an ion exchanger-column (600 ml, IR 120, H ⁺ -form). Subsequently it is washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, and the solid that forms is filtered off with suction, washed several times with diethyl ether and dried in vacuo.
Yield 15.5 g of colorless solid (59% of theory)
Elemental analysis:
Calculated value: C 41.32 H 5.55 N 12.05 I 21.83
Found: C 41.56 H 5.62 N 12.01 I 21.73.

e) 1,3,5-triiodo-2,4,6-tris- (2-aza-4-methyl-3-oxobutane-1,4-diyl- {10- [1,4,7-tris- ( Carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl]}, Gd complex) benzene 1,3,5-triiodo-2,4,6-tris- (2-aza-4-methyl-) 3-oxobutane-1,4-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene 12.0 g (6. 9 mmol) is dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.7 g (10.4 mmol) of gadolinium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h with stirring, filtered and then precipitated with 10 g of ion exchanger (IRA 67 OH-form) with stirring for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 7.6 g of colorless solid (47% of theory)
Water content (Karl-Fischer): 5.2%
Elemental analysis (for water-free substances):
Calculated value: C 32.66 H 3.97 N 9.52 I 17.25 Gd 21.38
Found: C 32.78 H 3.99 N 9.45 I 17.21 Gd 21.19.

Example 11
a) 10- [4-carbamido-1-methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid-t-butyl ester THF 500 ml 7-g of 10- [4-carboxy-1-methyl-2-oxo-3-azabutyl] 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid-t-butyl ester (18.7 mmol) (DE 19549286 A1, Schering AG, (Example 2d)) and 16.8 g (130.5 mmol) of isobutyl chloroformate are added dropwise at −20 ° C. to a solution of 16.9 g (130.5 mmol) of diisopropylethylamine. Add. The mixture is subsequently stirred at −20 ° C. for 1 hour and carefully mixed with 20 ml of 25% aqueous ammonia. Stirring is carried out after 2 h at 0 ° C., the solvent is subsequently distilled off in vacuo and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 61.1 g of colorless solid (80% of theory)
Elemental analysis:
Calculated value: C 57.92 H 9.09 N 13.07
Found: C 58.11 H 9.12 N 12.99.

b) 1,3,5-triiodo-2,4,6-tris- (2,5-diaza-3,6-dioxo-7-methylheptane-1,7-diyl- {10- [1,4, 7-tris- (t-butyloxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene 10- [4-carbamido-1-methyl-2-oxo-3-azabutyl]- 44.6 g (70.6 mmol) of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid-t-butyl ester is dissolved in 500 ml of THF and hydrogenated at 0 ° C. under argon. Mix with 1.71 g (71 mmol) sodium and stir at room temperature for 1 h. Subsequently, a solution of 20.2 g (20 mmol) of 1,3,5-triiodo-2,4,6-tris- (toluenesulfonyloxy) methylbenzene in 150 ml of THF is added dropwise and stirred at reflux for 20 h. After cooling, the insoluble components are filtered off and concentrated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water each time. The organic phase is dried over sodium sulfate, the solvent is concentrated to dryness and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 15.1 g of colorless solid (31% of theory)
Elemental analysis:
Calculated value: C 50.62 H 7.37 N 10.42 I 15:73
Found: C, 50.79 H, 7.41 N, 10.44 I, 15.64.

c) 1,3,5-triiodo-2,4,6-tris- (2,5-diaza-3,6-dioxo-7-methylheptane-1,7-diyl- {10- [1,4, 7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene 1,3,5-triiodo-2,4,6-tris- (2,5-diaza-3 , 6-Dioxo-7-methylheptane-1,7-diyl- {10- [1,4,7-tris- (t-butyloxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl ]}) 18.2 g (7.5 mmol) of benzene are dissolved in 75 ml of dichloromethane, mixed at 0 ° C. with 75 ml of trifluoroacetic acid and stirred at 0 ° C. for 3 hours. The batch is poured into 500 ml of diethyl ether, the precipitated solid is filtered off, washed with 3 × 100 ml of diethyl ether and dried in vacuo.
Yield 14.1 g of colorless solid (98% of theory)
Elemental analysis:
Calculated value: C 41.39 H 5.53 N 13.16 I 19.88
Found: C 41.51 H 5.57 N 13.11 I 19.67.

d) 1,3,5-triiodo-2,4,6-tris- (2,5-diaza-3,6-dioxo-7-methylheptane-1,7-diyl- {10- [1,4, 7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl]}, Gd complex) benzene 1,3,5-triiodo-2,4,6-tris- (2,5 -Diaza-3,6-dioxo-7-methylheptane-1,7-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl ]}) 13.2 g (6.9 mmol) of benzene are dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.7 g (10.4 mmol) of gadolinium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h with stirring, filtered and then precipitated with 10 g of ion exchanger (IRA 67 OH-form) with stirring for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 10.2 g of colorless solid (58% of theory)
Water content (Karl-Fischer): 6.2%
Elemental analysis (for water-free substances):
Calculated value: C 33.34 H 4.07 N 10.60 I 16.01 Gd 19.84
Found: C 33.52 H 4.12 N 10.63 I 15.89 Gd 19.72.

Example 12
a) 10- (4-carbamido-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid-t-butyl ester 10-in 500 ml of THF (4-Carboxy-2-oxo-3-azabutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid-t-butyl ester 74.8 g (118.7 mmol) (DE To a solution of 19549286 A1, Schering AG, (Example 1i)) and 16.9 g (130.5 mmol) of diisopropylethylamine, 17.8 g (130.5 mmol) of isobutyl chloroformate are added dropwise at −20 ° C. The mixture is subsequently stirred at −20 ° C. for 1 hour and carefully mixed with 20 ml of 25% aqueous ammonia. Stirring is carried out after 2 h at 0 ° C., the solvent is subsequently distilled off in vacuo and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 55.9 g of colorless solid (75% of theory)
Elemental analysis:
Calculated value: C 57.30 H 8.98 N 13.36
Found: C 57.45 H 8.99 N 13.31.

b) 1,3,5-triiodo-2,4,6-tris- (2,5-diaza-3,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris -(T-Butyloxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene 10- (4-carbamido-2-oxo-3-azabutyl) -1,4,7,10 44.4 g (70.6 mmol) of tetraazacyclododecane-1,4,7-triacetic acid-t-butyl ester are dissolved in 500 ml of THF and 1.71 g (71 mmol) of sodium hydride under argon at 0 ° C. And stirred at room temperature for 1 h. Subsequently, a solution of 20.2 g (20 mmol) of 1,3,5-triiodo-2,4,6-tris- (toluenesulfonyloxy) methylbenzene in 150 ml of THF is added dropwise and stirred at reflux for 20 h. After cooling, the insoluble components are filtered off and concentrated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water each time. The organic phase is dried over sodium sulfate, the solvent is concentrated to dryness and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 16.2 g of colorless solid (34% of theory)
Elemental analysis:
Calculated value: C 50.00 H 7.25 N 10.60 I 16.01
Found: C 50.17 H 7.28 N 10.55 I 15.89.

c) 1,3,5-triiodo-2,4,6-tris- (2,5-diaza-3,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris -(Carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene 1,3,5-triiodo-2,4,6-tris- (2,5-diaza-3,6- Dioxoheptane-1,7-diyl- {10- [1,4,7-tris- (t-butyloxycarbonylmethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene17. 9 g (7.5 mmol) are dissolved in 75 ml of dichloromethane, mixed with 75 ml of trifluoroacetic acid at 0 ° C. and stirred at 0 ° C. for 3 hours. The batch is poured into 500 ml of diethyl ether, the precipitated solid is filtered off, washed with 3 × 100 ml of diethyl ether and dried in vacuo.
Yield 13.5 g of colorless solid (96% of theory)
Elemental analysis:
Calculated value: C 40.39 H 5.33 N 13.46 I 20.32
Found: C40.21 H 5.27 N 13.57 I 20.22.

d) 1,3,5-triiodo-2,4,6-tris- (2,5-diaza-3,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris -(Carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl]}, Gd complex) benzene 1,3,5-triiodo-2,4,6-tris- (2,5-diaza- 3,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) benzene 9 g (6.9 mmol) are dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.7 g (10.4 mmol) of gadolinium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h with stirring, filtered and then precipitated with 10 g of ion exchanger (IRA 67 OH-form) with stirring for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 10.6 g of colorless solid (61% of theory)
Water content (Karl-Fischer): 6.5%
Elemental analysis (for water-free substances):
Calculated: C 32.39 H 3.88 N 10.79 I 16.30 Gd 20.19.
Found: C, 32.51 H, 3.91 N, 10.75, 16.16 Gd, 20.01.

Example 13
a) 2,4,6-triiodo-1,3,5-tris- (2-tert-butoxycarbonylaminoethoxymethyl) benzene 1,3,5-triiodo-2,4,6-trishydroxymethylbenzene 50. Toluenesulfonic acid-2-t dissolved in 250 ml toluene at room temperature in a mixture of 0 g (91.4 mmol) and 3 g (8.7 mmol) tetrabutylammonium hydrogen sulfate in 200 ml 32% NaOH solution and 300 ml toluene 142 g (450 mmol) of butoxycarbonylaminoethyl ester (Canne et al., Tetrahedron Letters, 38, 1997, 3361) are added dropwise and subsequently stirred for 12 h. Mix with 300 ml of water and extract twice with 300 ml each of toluene. The combined organic phases are dried over sodium sulfate, the solvent is concentrated to dryness and chromatographed on silica gel (eluent hexane / ethyl acetate 10: 1). Fractions containing product are combined and evaporated.
Yield 28.6 g of colorless solid (32% of theory)
Elemental analysis:
Calculated value: C 36.94 H 4.96 N 4.31 I 37.75
Found: C, 36.98 H, 4.90, N, 4.27 and 37.64.

b) 2,4,6-triiodo-1,3,5-tris- (aminoethoxymethyl) benzene 2,4,6-triiodo-1,3,5-tris- (2-tert-butoxycarbonylaminoethoxymethyl) ) 24.4 g (25 mmol) of benzene are dissolved in 100 ml of dichloromethane, mixed at 0 ° C. with 100 ml of trifluoroacetic acid and stirred at 0 ° C. for 3 hours. The batch is poured into 500 ml of diethyl ether, the solid formed in this case is filtered off with suction and washed several times with diethyl ether. The residue is dissolved in 100 ml water and 100 ml dichloromethane and 32% NaOH solution is added with vigorous stirring until a pH value of 10 is reached. The organic phase is separated, the aqueous phase is extracted 3 times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulphate and concentrated to dryness.
Yield 14.7 g of colorless solid (87% of theory)
Elemental analysis:
Calculated value: C 26.69 H 3.58 N 6.22 I 56.39
Found: C 26.78 H 3.55 N 6.16 I 56.27.

c) 2,4,6-Triiodo-1,3,5-tris- {10- [1,4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl] Aminoethoxymethyl} benzene In a solution of 15.9 g (23.5 mmol) 2,4,6-triiodo-1,3,5-tris- (aminoethoxymethyl) benzene in 400 ml DMF, 1,4,7-tris- (Benzyloxycarbonyl) -10- (carboxymethyl) -1,4,7,10-tetraazacyclododecane 44.6 g (70.6 mmol), triethylamine 21 ml (164 mmol), dicyclohexylcarbodiimide 14.6 g (70.5 mmol) And 8.1 g (70.5 mmol) of N-hydroxysuccinimide are added and stirred at room temperature for 20 h. Insoluble components are filtered off and concentrated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water each time. The organic phase is dried over sodium sulfate, the solvent is concentrated to dryness and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 29g of colorless solid (49% of theory)
Elemental analysis:
Calculated value: C 55.78 H 5.52 N 9.34 I 15.11
Found: C 55.91 H 5.62 N 9.26 I 14.89.

d) 2,4,6-triiodo-1,3,5-tris- [10- (1,4,7,10-tetraazacyclododecanyl) aminoethoxymethyl] benzene 2,4,6-triiodo-1 , 3,5-tris- {10- [1,4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl] aminoethoxymethyl} benzene 20 g (7.9 mmol) Is carefully mixed with 140 ml HBr / AcOH (33%) at 0-5 ° C. and stirred at room temperature for 3 h. The reaction mixture is subsequently poured into 800 ml of diethyl ether, and the solid that forms is filtered off with suction and washed with diethyl ether several times. The residue is dissolved in 100 ml water and 100 ml dichloromethane and 32% NaOH solution is added with vigorous stirring until a pH value of 10 is reached. The organic phase is separated, the aqueous phase is extracted 3 times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulphate and concentrated to dryness.
Yield 10.1 g of colorless solid (97% of theory)
Elemental analysis:
Calculated value: C 41.20 H 6.45 N 16.01 I 29.02
Found: C 41.09 H 6.42 N 15.98 I 28.87.

e) 2,4,6-triiodo-1,3,5-tris- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl] amino Ethoxymethyl} benzene 1,4,6-triiodo-1,3,5-tris- [10- (1,4,7,10-tetraazacyclododecanyl) aminoethoxymethyl] benzene 17.7 g (13.5 mmol) ) Is dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid is added and adjusted to a pH value of 9.5 with 32% NaOH at 60 ° C. Heat to 70 ° C. for 10 hours, during which time the pH value of the reaction mixture is continuously adjusted to 9.5. After cooling to room temperature, the pH is adjusted to 1 with concentrated HCl and the solution is evaporated in vacuo. The residue is stirred and precipitated with 250 ml of methanol, insoluble components are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and added onto an ion exchanger-column (600 ml, IR 120, H ⁺ -form). Subsequently it is washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, and the solid that forms is filtered off with suction, washed several times with diethyl ether and dried in vacuo.
Yield 14.4 g of colorless solid (58% of theory)
Elemental analysis:
Calculated value: C 41.25 H 5.60 N 11.45 I 20.76
Found: C 41.20 H 5.48 N 11.51 I 20.59.

f) 2,4,6-triiodo-1,3,5-tris- {10- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex] aminoethoxymethyl} benzene 2,4,6-triiodo-1,3,5-tris- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetra Azacyclododecanyl] aminoethoxymethyl} benzene 12.7 g (6.9 mmol) is dissolved in 100 ml water and acidified by addition of 3 ml acetic acid. Add 3.7 g (10.4 mmol) of gadolinium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h with stirring, filtered and then precipitated with 10 g of ion exchanger (IRA 67 OH-form) with stirring for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 7.4 g of colorless solid (44% of theory)
Water content (Karl-Fischer): 5.9%
Elemental analysis (for water-free substances):
Calculated value: C 32.94 H 4.08 N 9.15 I 16.57 Gd 20.54
Found: C 33.21 H 4.12 N 9.17 I 16.35 Gd 20.31.

Example 14
a) 2,4,6-Triiodo-5- [2- (2,2,2-trifluoroacetylamino) -acetylamino] -isophthalic acid dichloride 14.5 ml (200 mmol) of thionyl chloride was added at 0 ° C. over 1 hour. To a solution of 34.2 g (200 mmol) of glycine trifluoroacetate in 200 ml of dimethylacetamide. Subsequently, 23.8 g (40 mmol) of 5-amino-2,4,6-triiodoisophthalic acid dichloride (DE 2943777, Schering AG, (priority: October 26, 1979)) at room temperature is added at room temperature. For 4 days. The reaction mixture is poured into 5 l of ice water and the precipitated solid is filtered off. For further purification, the filter residue is dissolved in 1000 ml of ethyl acetate, extracted by shaking twice with saturated sodium hydrogen carbonate solution, the organic phase is dried over sodium sulphate and the solvent is evaporated in vacuo.
Yield: 29.3 g of colorless solid (97% of theory)
Elemental analysis:
Calculated value: C 19.25 H 0.54 N 3.74
Found: C 19.39 H 0.57 N 3.72.

b) 5- (2-Aminoacetylamino) -N, N-bis- (2-aminoethyl) -2,4,6-triiodoisophthalamide 2,4,6-triiodo-5 in 100 ml of tetrahydrofuran A solution of 10 g (13.3 mmol) of [2- (2,2,2-trifluoroacetylamino) -acetylamino] -isophthalic acid dichloride was added dropwise to 26.7 ml (399 mmol) of ethylenediamine at room temperature over 1 h, 14 h After stirring. The precipitated solid is filtered off, post-washed with ethanol, taken up in 100 ml of water and adjusted to a pH value of 8.0 using 1M lithium hydroxide solution. After evaporation in vacuo, recrystallize from ethanol.
Yield: 6.4 g of colorless solid (68% of theory)
Elemental analysis:
Calculated value: C 24.02 H 2.74 N 12.01 I 54.38
Found: C 24.276 H 2.79 N 11.98 I 54.25.

c) 2,4,6-triiodo-5- (3,6-diaza-1,4,7-trioxo-8-methyloctane-1,8-diyl- {10- [1,4,7-tris- (Carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]}) aminoisophthalic acid-N, N-bis- (3,6-diaza-4,7-dioxo-8- Methyloctane-1,8-diyl- {10- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]}) amide 10- [ 4-carboxy-2-oxo-3-aza-1-methylbutyl] 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid Gd complex 9.6 g (15.2 mmol) (WO 98/24775, Schering AG, (Example 1)) in 100 ml DMSO Suspension was mixed with N- hydroxysuccinimide 1.96 g (17 mmol) and dicyclohexylcarbodiimide 3.3 g (16 mmol), it is of 1 hour preactivation. Subsequently mixed with 2.4 g (3.4 mmol) of 5- (2-aminoacetylamino) -N, N-bis- (2-aminoethyl) -2,4,6-triiodoisophthalic acid amide at room temperature. Stir under nitrogen for 3 days. Insoluble components are filtered off and the solution is poured into 1000 ml of acetone. The solid which precipitates at this time is filtered off and washed little by little with 300 ml of acetone and 100 ml of diethyl ether. The residue is taken up in 200 ml of water, stirred for 2 h with 30 g of ion exchanger (IRA 67 OH-form) and filtered off. It is subsequently precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h with stirring, filtered off, mixed with 2 g of activated carbon, warmed to 60 ° C. for 2 hours, filtered off and the solution is concentrated to 100 ml. In order to remove the remaining dimethyl sulfoxide, the solution is poured into 1000 ml of acetone and the precipitated precipitate is filtered off. The residue is dissolved in 250 ml of water, the conductivity is adjusted to a value of 0.005 mS (pH = 7.0) with a slight ion exchanger (H-form and OH-form), filtered off, Evaporate in vacuum.
Yield: 5.7 g of colorless solid (62% of theory)
Water content (Karl-Fischer): 5.7%
Elemental analysis (for water-free substances):
Calculated value: C 33.64 H 4.09 N 11.60 I 15.02 Gd 18.61
Found: C 33.77 H 4.13 N 11.54 I 15.00 Gd 18.53.

Example 15
a) 2,4,6-triiodo-5- (3,6-diaza-1,4,7-trioxooctane-1,8-diyl- {10- [1,4,7-tris- (carboxylato) Methyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]}) aminoisophthalic acid-N, N-bis- (3,6-diaza-4,7-dioxooctane-1,8 -Diyl- {10- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]}) amide 10- [4-carboxy-2- 9.4 g (15.2 mmol) of Gd complex of oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (WO 98/24775, Schering AG, (example) 11)) is suspended in 100 ml of DMSO and N-hydroxysucci Mixed with imide 1.96 g (17 mmol) and dicyclohexylcarbodiimide 3.3 g (16 mmol), it is of 1 hour preactivation. Subsequently mixed with 2.4 g (3.4 mmol) of 5- (2-aminoacetylamino) -N, N-bis- (2-aminoethyl) -2,4,6-triiodoisophthalamide, at room temperature. Stir under nitrogen for 3 days. Insoluble components are filtered off and the solution is poured into 1000 ml of acetone. The solid which precipitates at this time is filtered off and washed little by little with 300 ml of acetone and 100 ml of diethyl ether. The residue is taken up in 200 ml of water, precipitated with stirring with 30 g of ion exchanger (IRA 67 OH-form) for 2 h and filtered off. It is subsequently precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h with stirring, filtered off, mixed with 2 g of activated carbon, warmed to 60 ° C. for 2 hours, filtered off and the solution is concentrated to 100 ml. In order to remove the remaining dimethyl sulfoxide, the solution is poured into 1000 ml of acetone and the precipitated precipitate is filtered off. The residue is dissolved in 250 ml of water, the conductivity is adjusted to a value of 0.005 mS (pH = 7.0) with a slight ion exchanger (H-form and OH-form), filtered off, Evaporate in vacuum.
Yield: 6.1 g of colorless solid (67% of theory)
Water content (Karl-Fischer): 6.4%
Elemental analysis (for water-free substances):
Calculated value: C 32.76 H 3.92 N 11.80 I 15.27 Gd 18.92
Found: C 32.91 H 3.98 N 11.81 I 15.11 Gd 18.67.

Example 16
a) 2,4,6-Triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) -1 , 4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7 -Tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]}) amide 5- (2-aminoacetylamino) -N, N-bis- (2-amino in 446 ml of DMF (Ethyl) -2,4,6-triiodoisophthalic acid amide (16.5 g, 23.5 mmol) was suspended in 1,4,7-tris- (benzyloxycarbonyl) -10- (carboxymethyl) -1, 4,7,10-tetraaza Kurododekan 44.6 g (70.6 mmol), triethylamine 21 ml (164 mmol), was added dicyclohexylcarbodiimide 14.6 g (70.5 mmol) and N- hydroxysuccinimide 8.1 g (70.5 mmol), to 20h stirring at room temperature. Insoluble components are filtered off and concentrated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water each time. The organic phase is dried over sodium sulfate, the solvent is concentrated to dryness and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 30.5 g of colorless solid (51% of theory)
Elemental analysis:
Calculated value: C 54.76 H 5.27 N 9.91 I 14.96
Found: C, 54.99 H, 5.35 N, 9.87 I, 14.65.

b) 2,4,6-Triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]} ) Aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) amide 2, 4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) -1,4,7 , 10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- ( Benzyloxycarbonyl) -1,4,7,10-tetraazacyclodode Canyl]}) amide 20 g (7.9 mmol) is carefully mixed at 0-5 ° C. with 140 ml HBr / AcOH (33%) and stirred at room temperature for 3 h. The reaction mixture is subsequently poured into 800 ml of diethyl ether, and the solid that forms is filtered off with suction and washed with diethyl ether several times. The residue is dissolved in 100 ml water and 100 ml dichloromethane and 32% NaOH solution is added with vigorous stirring until a pH value of 10 is reached. The organic phase is separated, the aqueous phase is extracted 3 times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulphate and concentrated to dryness.
Yield 10.1 g of colorless solid (96% of theory)
Elemental analysis:
Calculated value: C 39.53 H 5.96 N 18.86 I 28.48
Found: C 39.44 H 5.9 N 18.91 I 28.51.

c) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1, 4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7- Tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5 -Diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- { 10- [1,4,7,10-tetraazacyclododecanyl]}) amino 18.0 g (13.5 mmol) is dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid is added and adjusted to a pH value of 9.5 with 32% NaOH at 60 ° C. Heat to 70 ° C. for 10 hours, during which time the pH value of the reaction mixture is continuously adjusted to 9.5. After cooling to room temperature, the pH is adjusted to 1 with concentrated HCl and the solution is evaporated in vacuo. The residue is stirred and precipitated with 250 ml of methanol, insoluble components are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and added onto an ion exchanger-column (600 ml, IR 120, H ⁺ -form). Subsequently it is washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, and the solid that forms is filtered off with suction, washed several times with diethyl ether and dried in vacuo.
Yield 15.3 g of colorless solid (61% of theory)
Elemental analysis:
Calculated value: C 40.05 H 5.26 N 13.56 I 20.65
Found: C 40.22 H 5.29 N 13.49 I 20.56.

d) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxylatomethyl) -1 , 4,7,10-tetraazacyclododecanyl, Gd complex]}) aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1, 4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]}) amide 2,4,6-triiodo-5- (3-aza-1,4 -Dioxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-di Yl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide 12.8 g (6.9 mmol) dissolved in 100 ml of water And acidified by addition of 3 ml acetic acid. Add 3.7 g (10.4 mmol) of gadolinium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h with stirring, filtered and then precipitated with 10 g of ion exchanger (IRA 67 OH-form) with stirring for 2 h. Filter, mix with 2 g of activated carbon, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 8.3 g of colorless solid (48% of theory)
Water content (Karl-Fischer): 6.9%
Elemental analysis (for water-free substances):
Calculated value: C 32.07 H 3.82 N 10.86 I 16.40 Gd 20.32
Found: C, 32.21 H, 3.85 N, 10.89 I, 16.25 Gd, 20.19.

Example 17
a) 2,4,6-triiodo-5- (3-aza-1,4-dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) ) -1,4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-5-methyl-4-oxopentane-1,5-diyl- {10 -[1,4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]}) amide 5- (2-aminoacetylamino) -N, N in 446 ml of DMF -A suspension of 16.5 g (23.5 mmol) of bis- (2-aminoethyl) -2,4,6-triiodoisophthalamide is added to 1,4,7-tris- (benzyloxycarbonyl) -10. -(1-carboxyethyl) 1,4,7,10-tetraazacyclododecane 45.7 g (70.6 mmol), triethylamine 21 ml (164 mmol), dicyclohexylcarbodiimide 14.6 g (70.5 mmol) and N-hydroxysuccinimide 8.1 g (70.5 mmol) And stirred at room temperature for 20 h. Insoluble components are filtered off and concentrated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water each time. The organic phase is dried over sodium sulfate, the solvent is concentrated to dryness and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 28.6 g of colorless solid (47% of theory)
Elemental analysis:
Calculated value: C 55.27 H 5.42 N 9.75 I 14.72
Found: C 55.34 H 5.44 N 9.79 I 14.65.

b) 2,4,6-triiodo-5- (3-aza-1,4-dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododeca] Nyl]}) aminoisophthalic acid-N, N-bis- (3-aza-5-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododeca] Nyl]}) amide 2,4,6-triiodo-5- (3-aza-1,4-dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7-tris- ( Benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-5-methyl-4-oxopentane-1,5-diyl -{10- [1,4,7-tris- (benzyloxycal Bonyl) -1,4,7,10-tetraazacyclododecanyl]}) amide 20 g (7.7 mmol) is carefully mixed with 140 ml HBr / AcOH (33%) at 0-5 ° C. and stirred at room temperature for 3 h. To do. The reaction mixture is subsequently poured into 800 ml of diethyl ether, and the solid that forms is filtered off with suction and washed with diethyl ether several times. The residue is dissolved in 100 ml water and 100 ml dichloromethane and 32% NaOH solution is added with vigorous stirring until a pH value of 10 is reached. The organic phase is separated, the aqueous phase is extracted 3 times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulphate and concentrated to dryness.
Yield 10.2 g of colorless solid (96% of theory)
Elemental analysis:
Calculated value: C 40.94 H 6.21 N 18.28 I 27.61
Found: C 41.13 H 6.17 N 18.32 I 27.47.

c) 2,4,6-triiodo-5- (3-aza-1,4-dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-5-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) amide 2,4,6-triiodo-5- (3-aza-1,4- Dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) aminoisophthalic acid-N, N-bis- (3-aza-5 Methyl-4-oxopentane-1,5-diyl- {10- [1,4 , 7,10-tetraazacyclododecanyl]}) amide 18.6 g (13.5 mmol) is dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid is added and 32% NaOH at 60 ° C. To adjust the pH value to 9.5. Heat to 70 ° C. for 10 hours, during which time the pH value of the reaction mixture is continuously adjusted to 9.5. After cooling to room temperature, the pH is adjusted to 1 with concentrated HCl and the solution is evaporated in vacuo. The residue is stirred and precipitated with 250 ml of methanol, the insoluble components are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and added onto an ion exchanger-column (600 ml, IR 120, H ⁺ -form). Subsequently it is washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, and the solid that forms is filtered off with suction, washed several times with diethyl ether and dried in vacuo.
Yield 14.1 g of colorless solid (55% of theory)
Elemental analysis:
Calculated value: C 41.06 H 5.46 N 13.26 I 20.02
Found: C 41.34 H 5.52 N 13.31 I 19.69.

d) 2,4,6-triiodo-5- (3-aza-1,4-dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7-tris- (carboxylatomethyl) ) -1,4,7,10-tetraazacyclododecanyl, Gd complex]}) aminoisophthalic acid-N, N-bis- (3-aza-5-methyl-4-oxopentane-1,5-diyl -{10- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]}) amide 2,4,6-triiodo-5- ( 3-aza-1,4-dioxo-5-methylpentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododeca Nyl]}) aminoisophthalic acid-N, N-bis- (3- Aza-5-methyl-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) 13.1 g (6.9 mmol) of amide is dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.7 g (10.4 mmol) of gadolinium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h with stirring, filtered and then precipitated with 10 g of ion exchanger (IRA 67 OH-form) with stirring for 2 h. Filter, mix with 2 g of activated charcoal, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 7.6 g of colorless solid (44% of theory)
Water content (Karl-Fischer): 5.3%
Elemental analysis (for water-free substances):
Calculated value: C 33.02 H 4.01 N 10.66 I 16.10 Gd 19.96
Found: C 33.34 H 4.08 N 10.62 I 16.01 Gd 19.82.

Example 18
a) 2,4,6-Triiodo-5- {methyl [2- (2,2,2-trifluoroacetylamino) -acetyl] amino} -isophthalic acid dichloride 14.5 ml (200 mmol) of thionyl chloride at 0 ° C Add dropwise over 1 hour to a solution of 34.2 g (200 mmol) of glycine trifluoroacetate in 200 ml of dimethylacetamide. Subsequently, 24.4 g (40 mmol) of 5-amino-2,4,6-triiodoisophthalic acid dichloride (EP 0033426, Sovak, 1/80 US) are added at 0 ° C. and stirred at room temperature for 4 days. The reaction mixture is poured into 5 l of ice water and the precipitated solid is filtered off. For further purification, the filter residue is dissolved in 1000 ml of ethyl acetate, extracted by shaking twice with saturated sodium hydrogen carbonate solution, the organic phase is dried over sodium sulphate and the solvent is evaporated in vacuo.
Yield: 28.7 g of colorless solid (94% of theory)
Elemental analysis:
Calculated value: C 20.47 H 0.79 N 3.67
Found: C20.52H0.77N 3.71.

b) 5-[(2-Aminoacetyl) -methylamino] -N, N-bis- (2-aminoethyl) -2,4,6-triiodoisophthalamide 2,4,6- in 100 ml of tetrahydrofuran A solution of 10 g (13.1 mmol) of triiodo-5- {methyl- [2- (2,2,2-trifluoroacetylamino) -acetyl] -amino} -isophthalic acid dichloride was added to 26.7 ml (399 mmol) of ethylenediamine for 1 h. At room temperature and stirred after 14 h. The precipitated solid is filtered off, post-washed with ethanol, taken up in 100 ml of water and adjusted to a pH value of 8.0 using 1M lithium hydroxide solution. After evaporation in vacuo, recrystallize from ethanol.
Yield: 7.3 g of colorless solid (78% of theory)
Elemental analysis:
Calculated value: C 25.23 H 2.96 N 11.77 I 53.31
Found: C 25.44 H 2.98 N 11.81 I 53.09.

c) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) -1 , 4,7,10-tetraazacyclododecanyl]})-methylaminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4 , 7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 5-[(2-aminoacetyl) -methylamino] -N, N in 446 ml DMF A suspension of 16.8 g (23.5 mmol) of bis- (2-aminoethyl) -2,4,6-triiodoisophthalamide has a concentration of 1,4,7-tris- (benzyloxycarbonyl) -10- (Carboxymethyl) -1,4 7,10-tetraazacyclododecane 44.6 g (70.6 mmol), triethylamine 21 ml (164 mmol), dicyclohexylcarbodiimide 14.6 g (70.5 mmol) and N-hydroxysuccinimide 8.1 g (70.5 mmol) were added, Stir at room temperature for 20 h. Insoluble components are filtered off and concentrated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water each time. The organic phase is dried over sodium sulfate, the solvent is concentrated to dryness and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 34.9 g of colorless solid (58% of theory)
Elemental analysis:
Calculated value: C 54.93 H 5.32 N 9.86 I 14.88
Found: C 55.12 H 5.39 N 9.81 I 14.72.

d) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]} ) -Methylaminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]})- Amide 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) -1, 4,7,10-tetraazacyclododecanyl]}) methylaminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7 -Tris- (benzyloxycarbonyl) -1,4,7,10-teto Raazacyclododecanyl]})-amide 20 g (7.8 mmol) is carefully mixed with 140 ml HBr / AcOH (33%) at 0-5 ° C. and stirred at room temperature for 3 h. The reaction mixture is subsequently poured into 800 ml of diethyl ether, and the solid that forms is filtered off with suction and washed with diethyl ether several times. The residue is dissolved in 100 ml water and 100 ml dichloromethane and 32% NaOH solution is added with vigorous stirring until a pH value of 10 is reached. The organic phase is separated, the aqueous phase is extracted 3 times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulphate and concentrated to dryness.
Yield 10.0 g of colorless solid (95% of theory)
Elemental analysis:
Calculated value: C 40.01 H 6.04 N 18.66 I 28.18
Found: C 40.19 H 6.07 N 18.62 I 28.03.

e) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1, 4,7,10-tetraazacyclododecanyl]})-methylaminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4, 7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane- 1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]})-methylaminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1, 5-diyl- {10- [1,4,7,10-tetraazacyclod Decanyl]})-amide 18.2 g (13.5 mmol) was dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid was added, pH 9.5 with 32% NaOH at 60 ° C. Adjust to the value. Heat to 70 ° C. for 10 hours, during which time the pH value of the reaction mixture is continuously adjusted to 9.5. After cooling to room temperature, the pH is adjusted to 1 with concentrated HCl and the solution is evaporated in vacuo. The residue is stirred and precipitated with 250 ml of methanol, the insoluble components are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and added onto an ion exchanger-column (600 ml, IR 120, H ⁺ -form). Subsequently it is washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, and the solid that forms is filtered off with suction, washed several times with diethyl ether and dried in vacuo.
Yield 15.0 g of colorless solid (59% of theory)
Elemental analysis:
Calculated value: C 40.39 H 5.33 N 13.46 I 20.32
Found: C 40.53 H 5.37 N 13.41 I 20.17.

f) 2,4,6-triiodo-5- (3-aza-1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxylatomethyl) -1 , 4,7,10-tetraazacyclododecanyl, Gd complex]})-methylaminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [ 1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]})-amide 2,4,6-triiodo-5- (3-aza- 1,4-dioxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]})-methylamino Isophthalic acid-N, N-bis- (3-aza-4-oxope Ntan-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 12.9 g (6.9 mmol) ) Is dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.7 g (10.4 mmol) of gadolinium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h with stirring, filtered and then precipitated with 10 g of ion exchanger (IRA 67 OH-form) with stirring for 2 h. Filter, mix with 2 g of activated charcoal, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 8.7 g of colorless solid (51% of theory)
Water content (Karl-Fischer): 5.8%
Elemental analysis (for water-free substances):
Calculated value: C 32.39 H 3.88 N 10.79 I 16.30 Gd 20.19
Found: C 32.48 H 3.91 N 10.76 I 16.21 Gd 20.08.

Example 19
a) 5- [3- (2-Aminoethyl) -ureido] -N, N-bis- (2-aminoethyl) -2,4,6-triiodoisophthalamide 5-amino-2 in 250 ml dioxane , 4,6-Triiodoisophthalic acid dichloride 29.8 g (50 mmol) (DE 2943777, Schering AG, (priority: October 26, 1979)) carefully added 100 ml of a 2M solution of phosgene in toluene And heated to 60 ° C. for 24 hours. The solution is subsequently evaporated in vacuo at 80 ° C., with the gas being passed through a 20% aqueous NaOH solution. The residue is dissolved in 200 ml of tetrahydrofuran, added dropwise to 66.9 ml (1.0 mol) of ethylenediamine at room temperature over 1 h and stirred after 24 h. The precipitated solid is filtered off, post-washed with ethanol, taken up in 200 ml of water and adjusted to a pH value of 8.0 using 1M lithium hydroxide solution. After evaporation in vacuo, recrystallize from ethanol.
Yield: 19.4 g of colorless solid (53% of theory)
Elemental analysis:
Calculated value: C 24.71 H 3.04 N 13.45 I 52.22
Found: C 24.91 H 3.09 N 13.36 I 51.97.

b) 2,4,6-triiodo-5- (2,5-diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]})-aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1, 4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 5- [3- (2-aminoethyl) -ureido] -N in 446 ml of DMF , N-bis- (2-aminoethyl) -2,4,6-triiodoisophthalamide 17.1 g (23.5 mmol) in a suspension of 1,4,7-tris- (benzyloxycarbonyl)- 10- (carboxymethyl) -1,4,7 , 10-tetraazacyclododecane 44.6 g (70.6 mmol), triethylamine 21 ml (164 mmol), dicyclohexylcarbodiimide 14.6 g (70.5 mmol) and N-hydroxysuccinimide 8.1 g (70.5 mmol) are added. For 20 h. Insoluble components are filtered off and concentrated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water each time. The organic phase is dried over sodium sulfate, the solvent is concentrated to dryness and the residue is chromatographed on silica gel (eluent dichloromethane / methanol 20: 1). Fractions containing product are combined and evaporated.
Yield 32.7 g of colorless solid (54% of theory)
Elemental analysis:
Calculated value: C 54.61 H 5.33 N 10.24 I 14.80
Found: C 54.81 H 5.35 N 10.13 I 14.72.

c) 2,4,6-triiodo-5- (2,5-diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7,10-tetraazacyclododecanyl) ]})-Aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]}) -Amido 2,4,6-triiodo-5- (2,5-diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris- (benzyloxycarbonyl) -1,4,7,10-tetraazacyclododecanyl]})-aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1, 4,7-tris- (benzyloxycarbonyl) -1,4,7,10-te Traazacyclododecanyl]})-amide 25.7 g (10 mmol) is carefully mixed with 140 ml HBr / AcOH (33%) at 0-5 ° C. and stirred at room temperature for 3 h. The reaction mixture is subsequently poured into 800 ml of diethyl ether, and the solid that forms is filtered off with suction and washed with diethyl ether several times. The residue is dissolved in 100 ml water and 100 ml dichloromethane and 32% NaOH solution is added with vigorous stirring until a pH value of 10 is reached. The organic phase is separated, the aqueous phase is extracted 3 times with 50 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulphate and concentrated to dryness.
Yield 12.8 g of colorless solid (94% of theory)
Elemental analysis:
Calculated value: C 39.57 H 6.05 N 19.48 I 27.87
Found: C 39.71 H 5.9 N 19.56 I 27.61.

d) 2,4,6-triiodo-5- (2,5-diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris- (carboxymethyl)- 1,4,7,10-tetraazacyclododecanyl]})-aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4 , 7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 2,4,6-triiodo-5- (2,5-diaza-1,6-di Oxoheptane-1,7-diyl- {10- [1,4,7,10-tetraazacyclododecanyl]})-aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane- 1,5-diyl- {10- [1,4,7,10-tetraazacyclod Decanyl]})-amide 18.4 g (13.5 mmol) was dissolved in 75 ml of water, 19.5 g (206.5 mmol) of chloroacetic acid was added, pH 9.5 with 32% NaOH at 60 ° C. Adjust to the value. Heat to 70 ° C. for 10 hours, during which time the pH value of the reaction mixture is continuously adjusted to 9.5. After cooling to room temperature, the pH value is adjusted to 1 with concentrated HCl and the solution is evaporated in vacuo. The residue is stirred and precipitated with 250 ml of methanol, the insoluble components are filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of water and added onto an ion exchanger-column (600 ml, IR 120, H ⁺ -form). Subsequently it is washed with 2 l of water and the acidic eluate is evaporated. The residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, and the solid that forms is filtered off with suction, washed several times with diethyl ether and dried in vacuo.
Yield 14.3 g of colorless solid (56% of theory)
Elemental analysis:
Calculated value: C 40.07 H 5.34 N 14.09 I 20.16
Found: C 40.24 H 5.31 N 13.99 I 19.98.

e) 2,4,6-triiodo-5- (2,5-diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]})-aminoisophthalic acid-N, N-bis- (3-aza-4-oxopentane-1,5-diyl- {10- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecanyl, Gd complex]})-amide 2,4,6-triiodo-5- (2,5 -Diaza-1,6-dioxoheptane-1,7-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]}) -Aminoisophthalic acid-N, N-bis- (3-aza-4-oxope Ntan-1,5-diyl- {10- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecanyl]})-amide 13.0 g (6.9 mmol) ) Is dissolved in 100 ml of water and acidified by addition of 3 ml of acetic acid. Add 3.7 g (10.4 mmol) of gadolinium oxide and heat at reflux for 6 h. After complexation is complete, the pH is adjusted to 7.4 with ammonia and chromatographed on silica gel (eluent: dichloromethane / methanol / ammonia: 10/10/1). Fractions containing the product are combined and precipitated with 10 g of ion exchanger (IR 267 H-form) for 2 h with stirring, filtered and then precipitated with 10 g of ion exchanger (IRA 67 OH-form) with stirring for 2 h. Filter, mix with 2 g of activated charcoal, heat to 60 ° C. for 2 hours, filter and freeze-dry.
Yield 7.1 g of colorless solid (41% of theory)
Water content (Karl-Fischer): 6.3%
Elemental analysis (for water-free substances):
Calculated value: C 32.19 H 3.90 N 11.32 I 16.19 Gd 20.07
Found: C 32.34 H 3.91 N 11.28 I 16.07 Gd 19.96.

Pharmacological Example CT Examination Using Example 1B The suitability of the above compound types was examined for Example 1B, illustratively using rat computed tomography (CT). A Siemens Somatom CR was available for CT examination. A 5 second image was created using a layer thickness of 2 mm and a tube voltage of 125 kV. Substance 1B was formulated as an aqueous solution with a concentration of 0.17 mol / L (corresponding to 145 mg (I + Gd) / mL).

  Male Wistar rats (body weight 400 g) were injected before intravenous injection (FIG. 1a) and after intravenous injection of 1B at a dose of 0.15 mmol / kg (corresponding to 127 mg (I + Gd) / kg) (FIG. 1). Scanned.

  Despite the small size of the test animals, very clear contrasting of blood-carrying blood vessels (A) and kidney cortex (N) is observed even with a small dose of 127 mg (I + Gd) did it. This early stage reflects renal cortical blood perfusion. The renal pelvis is already contrasted after 15 minutes in the parenchyma, which can be attributed to rapid renal excretion of the substance (FIG. 2).

MRT Examination Using Example 1B The same substance (1B) was examined using magnetic resonance tomography (MRT) as a contrast agent.

  MRT inspection was performed on a 1.5 T instrument (Siemens Symphonie with a 40 mT / m gradient). Wistar rats weighing 400 g were subjected to T1 weighing image sequences (angiography TR 2.54 ms, TE 1.12 ms and α = 40 ° or organ visualization TR 54 ms, TE 4.8 ms and α = 40 °). Used to inspect. Angiography (MRA, FIG. 3) was created 0-60 sec (p.i.) after injection and organ depictions (FIGS. 4a and b) 15 min after injection. Substance 1B was formulated as an aqueous solution with a concentration of 0.17 mol / L (corresponding to 0.5 mol Gd / L) and injected intravenously at a dose of 0.03 mmol or 0.1 mmol Gd / kg of substance.

  MRA delineates the aorta (Aorta, femoral artery) as well as the heart.

  In the overall image (FIG. 4b), a clear contrast of the liver (L) as well as the kidney (renal pelvis = N) can be identified. Similarly, the ureter (U) can be visualized, which also highlights rapid renal excretion of the substance.

  This combined CT and MR examination demonstrates the dual use of these new compound types. Excellent contrast enhancement has been demonstrated in CT as well as MR. For example, clinical use of these compounds in high-resolution MultiSlice CT (depicting cardiac coronary vessels) is possible. Subsequently, late MRT is performed for assessment of myocardial vitality. For this purpose, a second injection of contrast agent is unnecessary.

Phantom study using Example 3F compared to Gadovist and Iopromid Compared the relative X-ray attenuation of Example 3F to the equimolar concentrations of Iopromid and Gadobutrol, elements that give contrast (Gd + iodine) 0.3, 0.6 And at a concentration of 0.05, 0.1 and 0.2 mol / L of substance, equivalent to 1.2 mol / L. For this purpose, distilled water of the starting preparation (eg 3F-0.27M, 0.788mol / L Iopromid and Gadobutrol 1mol / L to an equivalent ^{Ultravist (R) 300mg l / mL} ) dilutions well plates (Oster 3524) A phantom that was pipetted in was used. 1 ml of each dilution was pipetted into one well-plate each time, corresponding to a height of 0.5 cm. To simulate soft tissue absorption and radiation sclerosis of X-rays as in the in vivo situation, a well plate transferred with a complete pipette is placed on a horizontal patient table in a C-arm X-ray device (Stenoskop D6, General Electrics). Positioned above into the beam path, a plastic container with a 17 cm water column above it was placed on the well plate.

  X-ray images were recorded in a “High Puls” modality using a DSA X-ray machine Stenoskop D6 (General Electrics) with a 16 cm cesium filter / iodine amplifier and a 2 mm aluminum filter at various X-ray voltages.

  In order to optimize the image contrast at each anode voltage, all images were recorded after manual selection of the X-ray tube anode voltage and mA change.

  Stenoskop D6 images were then transferred to an image analyzer (Quantimet 500+, Leica) and rendered on a 256 gray scale. For quantitative gray value determination, a circular ROI (region of interest) was analyzed for each well and the background at each anode voltage was reduced.

  The measured gray values of Example 3F, Iopromid and Gabobutrol were applied for each concentration and a linear area analysis was performed. The increase in the compensation line was then calculated to determine the linear ratio between the various contrast agents.

  A typical X-ray image of the phantom is depicted in FIG.

  The ratio between the concentrations of Example 3F, Iopromid and Gadobutrol was linear in all cases. Evaluation showed a significantly higher X-ray absorption of Example 3F than Iopromid and Gadobutrol at equimolar concentrations (FIG. 5).

  In the evaluation of the X-ray image, at 3OkV and equimolar concentration, Example 3F showed an X-ray absorption 3.08 times higher than that of Iopromid and 3.77 times higher than that of Gadobutrol. Even higher differences in the X-ray absorption of Example 3F can be predicted for higher anode voltages as used in modern X-ray CT methods (Helicordal and Multiline-CT). The additional radiation curing that occurs in the in vivo situation additionally favors elements such as Gd, Dy, Yb or Bi.

  Phantom studies have demonstrated that Example 3F has excellent X-ray absorption and is suitable for use in modern DSA and CT, particularly multiline-CT.

Partition coefficient The partition coefficient of Example 3F was determined in Tris-HCl buffer at 1-butanol and pH 7.6 compared to Gadovist, Iopromid and Iotrolan. The contrast agent was dissolved in buffer at a final concentration of 0.1 mmol Gd / L and iodine-containing contrast agent was used at a starting concentration of 1 mg I / mL.

  Table 1: Partition coefficient of Example 3F compared to commercially available MR contrast agent and X-ray contrast agent

  The data in Table 1 shows that Example 3F is a very hydrophilic material with a slight butanol / water partition coefficient and, on the contrary, has a better value than the highly compatible MR contrast agent Gadovist. Prove that. In comparison, the commercially available iodine-containing compound Iopromid has much less hydrophilicity (0.051 vs. 0.0002) with a higher butanol / water partition coefficient up to 255 times.

IC-50 / LD-50 Correlation For the determination of IC-50, the neutral red test on epithelial cells of distal renal tubules was used. This test is also very helpful in predicting the LD-50 values of newly synthesized compounds with high accuracy.

The canine kidney renal distal renal tubular epithelial cell line MDCK (ECACC No. 85011435) was obtained from 10000 cells / well in Alpha MEM Eagle (10% fetal calf serum) at 37 ° C. and 5% CO ₂ , 95. Incubated with various examples 1B, 3F and 5F for 20 h at% atmospheric humidity. Neutral red was used as an indicator for cell activity and to measure lysosomal integrity, and to determine their contrast agent concentration at which a 50% reduction in cell activity (IC-50) occurred after 24 h. .

  Four independent replicates were tested for each concentration of contrast agent. The results are summarized in Table 2. It showed a strong increase in compatibility compared to the reference compound Gadovist for the MR contrast agent. The latter is a reference compound in the clinic and a contrast agent with proven superior compatibility. The highest compatibility was found at 1170 μmol Ieq / mL for Example 3F.

TABLE 2 Comparison of IC ₅₀ values between various examples according to the invention and Gadobutrol and predictable LD ₅₀ values in mice

CT images of male Wistar rats (body weight 400 g) before intravenous injection (a) and after intravenous injection of 1B at a dose of 0.15 mmol / kg (corresponding to 127 mg (I + Gd) / kg). CT image of rat 15 minutes after intravenous injection of 1B. MRA 7.5 seconds after intravenous injection of 1B for rats. Visualization of organs 15 minutes after injection. Example 3F Phantom X-ray image recorded using C-arm device Stenoskop D6 (General Electrics) at 60 and 110 kV anode voltage, showing a comparison of X-ray absorption of Gadobutrol and Iopromid. Relative X-ray absorption of Example 3F compared to Gadobutrol and Iopromid at various anode voltages of X-ray tubes (Stenoskop D6, General Electrics).

Claims (13)

Formula I

[Where:
Hal represents bromine or iodine,
A ¹ is a group —CONR ¹ — (CH ₂ ) _n —NR ² — (CO—CHZ ¹ —NH) _m —CO—CHZ ² —K,
_{^{-CONR 1 - (CH 2) p}} - (CONR 2 CH 2) m -CHOH-CH 2 -K,
_{-CH 2 O- (CH 2) p} -CHOH-CH 2 -K,
^{_{-CH 2 -O- (CH 2) n}} -NR 1 - (CO-CHZ 1 -NH) m -CO-CHZ 2 -K,
—CH ₂ —NR ¹ —CO— (CHZ ¹ —NH—CO) _m —CHZ ² —K
Represents
A ² is either have the same meaning as ^{A 1,} or the group ^-NR 1 -CO- in case have the ^{meanings A 1} is very first-mentioned _{^{(NR 1) m - (CH}} 2) p -NR 2 - (CO—CHZ ¹ —NH) _m —CO—CHZ ² —K may also be represented,
Here, R ¹ and R ² independently represent a hydrogen atom, a C ₁ -C ₂ -alkyl group or a monohydroxy-C ₁ -C ₂ -alkyl group,
Z ¹ and Z ² each independently represent a hydrogen atom or a methyl group,
n represents a number from 2 to 4,
m represents a number of 0 or 1, and p represents a number of 1 to 4,
K is the formula _{I A}

{Wherein X represents a hydrogen atom or a metal ion equivalent of atomic number 20 to 29, 39, 42, 44 or 57 to 83}, provided that at least two X are A metal complex which represents a metal ion equivalent and optionally presents a free carboxy group is optionally present as a salt of an organic and / or inorganic base or amino acid or amino acid amide]. A ¹ is,
_{-CONH (CH 2) 2; 3} NHCOCH 2 NHCOCH (CH 3) -,
_{-CONH (CH 2) 2; 3} NHCOCH 2 NHCOCH 2 -,
_{-CONH (CH 2) 2; 3} NHCOCH 2 -,
_{-CONH (CH 2) 2; 3} NHCOCH (CH 3) -,
_{-CONHCH 2 CH (OH) CH 2} -,
_{-CON (CH 3) CH 2 CH} (OH) CH 2 -,
_{-CH 2 OCH 2 CH (OH)} CH 2 -,
_{-CONHCH 2 CONHCH 2 CH (OH)} CH 2 -,
-CH ₂ NHCOCH ₂ -,
_{-CH 2 NHCOCH (CH 3) -} ,
-CH ₂ NHCOCH ₂ NHCOCH ₂ -,
_{-CH 2 NHCOCH 2 NHCOCH (CH 3} ) -,
_{-CH 2 O (CH 2) 2} NHCOCH 2 -,
_{-CON (CH 2 CH 2 OH (} CH 2) 2 NHCOCH 2 -,
_{-CH 2 O (CH 2) 2} N (CH 2 CH 2 OH) COCH 2 -
The metal complex according to claim 1, which represents a group of A ² is,
_{-NHCOCH 2 NHCOCH 2 NHCOCH (CH 3} ) -,
-NHCOCH ₂ NHCOCH ₂ NHCOCH ₂ -,
-NHCOCH ₂ NHCOCH ₂ -,
_{-NHCOCH 2 NHCOCH (CH 3) -} ,
_{-N (CH 3) COCH 2 NHCOCH} 2 -,
_{-NHCONH (CH 2) 2 NHCONH 2} -,
_{-NHCOCH 2 N (CH 2 CH 2} OH) COCH 2 -,
_{-N (CH 3) COCH 2 N} (CH 2 CH 2 OH) COCH 2 -
The metal complex according to claim 1, which represents   The metal complex according to claim 1, wherein X represents a metal ion equivalent having an atomic number of 21 to 29, 42, 44, 58 to 70.   The metal complex according to claim 4, wherein X represents a metal ion equivalent of gadolinium (III), dysprosium (III), europium (III), iron (III) or manganese (II) being ions.   A medicament comprising at least one metal complex of the general formula I according to claim 1, optionally together with additives commonly used in Galen Pharmaceuticals.   Use of at least one metal complex according to claim 1 for the manufacture of a medicament for X-ray diagnosis.   Use of at least one metal complex according to claim 4 for the manufacture of a medicament for MRT diagnosis.   A medicament comprising the metal complex according to claims 1 and 4, respectively, in a molar ratio of 2000: 1 to 1: 1, preferably 49: 1 to 4: 1.   The medicament according to claim 6, wherein the metal complex dissolved or suspended in water or physiological salt solution is present at a concentration of 0.001 to 1 mol / l.   For cerebral infarction and liver tumor or space-occupying course in the liver and X-ray and MR diagnosis of abdominal (including kidney) and muscle-skeletal-system tumors, and particularly preferably the compound is injected intra-arterial but also intravenous Use of at least one metal complex according to claim 1 for the manufacture of a medicament that can be used for the visualization of blood vessels after internal injection. A process for producing a metal complex of the general formula I according to claim 1,
a) Formula II

A triiodo- or tribromoaromatic compound represented by the general formula III

[Where:
C ^x O represents —COOH— or an activated carboxyl group,
W represents a protecting group or a —CH ₂ COOX′— group (where X ′ represents X or a protecting group), and —Y ¹ —NR ¹ —CO—B ¹ — represents —CO—NR ¹ — (CH ₂ ) _n —NR ² — (CO—CHZ ¹ —NH) _m —CO—CHZ ² — or —CH ₂ —O— (CH ₂ ) _n —NR ¹ — (CO—CHZ ¹ —NH) _m Represents the group A ^{1 in} the meaning of —CO—CHZ ² — and Y ² —NR ¹ —CO—B ¹ represents Y ¹ —NR ¹ —CO—B ¹ or Y ¹ —NR ¹ —CO—B ^{1 -NR} 1 -CO- if it has the meaning most initially mentioned _{^{(NR 1) m (CH 2}} ) p -NR 2 - (CO-CHZ 1 -NH) m -CO-CHZ 2 - also represents its B ¹ when the (as viewed from K) 1 or second of between -CO- and K on the carbonyl group Means that group, and Y ¹ or Y ² is reacted with a macrocyclic compound represented by a group of the lack of linker groups that are reduced by one imino group, removing the protecting group W optionally subsequently The group CH ₂ COOX is introduced in a manner known per se, or the protective group optionally representing X ′ is removed and subsequently atom numbers 20-29, 39, 42, 44 or 57-83 in a manner known per se. Reacting with a metal oxide or metal salt of the element of

A triiodo- or tribromo aromatic compound represented by the general formula V

Wherein, -C ^x O and X 'represents the meanings given above and ^-CO-NR 1 -Y ³ is _{^{-CONR 1 - (CH 2) p}} - (CONR 2 CH 2) m -CH (OH) CH ₂ — represents the meaning of group A ¹ , and therefore Y ³ represents —NR ¹ — (CH ₂ ) _p — (CONR ² CH ₂ ) _m —CH (OH) CH ₂ —. Reacting with the macrocycle and subsequently removing the protective group optionally representing X ′, and then metal oxides or metals of the atomic number 20-29, 39, 42, 44 or 57-83 in a manner known per se Reacting with a salt, or c) general formula VI

[Where:
A ¹ is the group

A triiodo- or tribromo aromatic compound represented by the general formula VII

[Wherein W ′ represents a hydrogen atom or a protecting group] is reacted with a cyclic compound (removing an optionally present protecting group, followed by a group —CH ₂ COOX in a manner known per se). Or a metal complex of the general formula I, where A ¹ is the meaning of the group —CH ₂ —O— (CH ₂ ) _p —CHOH—CH ₂ —, or d) Formula VIII

[Wherein Nucleofug represents a leaving group] A triiodo- or tribromo aromatic compound represented by the general formula IX

[Where:
R ¹ and W are as defined above, and B ² represents a macrocycle represented by the group — (CHZ ¹ —NHCO) _m —CHZ ² —] and subsequently described under a). As a result, a metal complex of the general formula I {where A ¹ is the meaning of the group —CH ₂ —NR ¹ —CO— (CHZ ¹ —NHCO) _m —CHZ ² ) is obtained. In this case, the acidic hydrogen atoms still present in the metal complexes of the general formula I thus optionally obtained in accordance with a) to d) are replaced by cations of inorganic or organic bases, amino acids or amino acid amides. A process for producing a metal complex of the general formula I according to claim 1, characterized in that   7. The method for producing a medicament according to claim 6, wherein the complex compound dissolved or suspended in water or a physiological salt solution is suitable for enteral administration or parenteral administration, optionally together with conventional additives in Galen Pharmaceutical. The method for producing a medicine according to claim 6, wherein

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