RU2425831C2 - Multimeric magnetic resonance contrast agents - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (II), consisting of a core and groups -R-L-X' attached to said core, nA(-R-L-X')n (II). A denotes an aromatic ring selected from [1,3,5]triazinane-2,4,6-trione ring or a benzene ring, possibly substituted with one or more C₁-C₃-alkyls; R denotes a benzene ring residue possibly substituted with C₁-C₃-alkyl, and R can be bonded to A through a group of formula

, where R^b denotes C₁-C₃-alkyl; L denotes a linker group - CZ¹Z²-CO-N(R^b)-*; where * denotes bonding of R to the said linker group, Z¹ and Z² denote hydrogen, or Z¹ denotes hydrogen and Z² denotes methyl, and R^b denotes H or C₁-C₃-alkyl; X' denotes a paramagnetic chelate consisting of chelator X and a paramagnetic metal ion M; where X denotes a residue of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), M denoets Gd³⁺; n equals 3. If A denotes a benzene ring, R can denote a cyclic group condensed with the core A, which corresponds to the following formula:

, where Qa denotes C(Rc)₂, and Rc denotes CH₂OCH₃; L and X' assume values given above. The invention also discloses a composition, use of the composition, a compound of formula (I), a method of producing the compound of formula (I) (versions) and a method of producing the compound of formula (II).

EFFECT: obtaining compounds which function well as magnetic resonance (MR) contrast agents in strong magnetic fields.

8 cl, 9 ex

Description

The invention relates to new compounds of formulas (I) and (II), compositions containing compounds of formula (II), and their use as contrast agents in magnetic resonance (MR) imaging (MRI) and magnetic resonance spectroscopy (MRS).

A signal in MR imaging is affected by a number of parameters, which can be divided into two main categories: parameters inherent in tissues, and visualization parameters selected by the user. The parameters inherent in tissues, which affect the intensity of the MR signal of a particular tissue, are mainly the density of protons, that is, the density of the hydrogen nuclei of this tissue, and its inherent relaxation times T ₁ and T ₂ . Other factors, such as flow, also affect the signal strength. The contrast between two adjacent tissues, such as a tumor and normal tissue, depends on the difference in signal between the two tissues. This difference can be maximized through the correct use of user-selectable parameters. User-selectable options that can affect the contrast of an MR image include selecting a pulse sequence, flip angles, echo time, repetition time, and the use of contrast agents.

Contrast agents are often used in MRI to improve image contrast. Contrast agents work by influencing the relaxation times T ₁ , T ₂ and / or T ₂ * and thereby the image contrast. By observing the dynamic behavior of the contrast agent, information related to perfusion, permeability and cell density, as well as other physiological parameters can be obtained.

In MRI, several types of contrast agents were used. As MR contrast agents, water-soluble paramagnetic metal chelates, for example gadolinium chelates such as Omniscan ™ (GE Healthcare), are widely used.

Due to their low molecular weight, they are very rapidly distributed in the extracellular space (i.e., in the blood and interstitium) when introduced into the vascular network. They are also relatively rapidly excreted from the body.

On the other hand, MR contrast agents of the blood pool, for example particles of superparamagnetic iron oxide, are stored in the vasculature for a long time. It has been proven that they are very useful for improving the contrast in the liver, as well as for detecting disturbances in the permeability of capillaries, for example, “flowing” walls of capillaries in tumors that result from tumor angiogenesis.

Existing paramagnetic metal chelates, which are used as MR contrast agents, have a low relaxivity in a 1.5 T magnetic field, which is the standard for most modern MR scanners. In 3 T systems, which are likely to dominate or at least make up a significant market share in the future, the internal contrast is lower, all T ₁ values are higher, and the equipment will be faster, so the need for a contrast agent with good performance at 3 T will be significant. In general, in the strong magnetic fields of modern MR scanners, that is, 1.5 T, 3 T or even higher, the longitudinal relaxability r1 of the contrast agents is worsened. This is due to the rapid rotational Brownian motion of small molecules in the solution, which leads to a weaker combination of the paramagnetic metal ion with water molecules in a magnetic field than might be expected.

By introducing paramagnetic metal chelates into larger molecules, such as various polymers, many attempts have been made to obtain contrast agents with high relaxation. These attempts have had limited success due to rapid internal rotations or segment movements. Another approach is paramagnetic metal chelates that bind or actually bind to proteins. However, such compounds have pharmacological and pharmacokinetic disadvantages, similar to the long time of excretion or the risk of interactions with drugs associated with the protein. In addition, leakage through the normal endothelium in the interstitium is still significant.

The present invention provides new compounds that function well as MR contrast agents in strong magnetic fields, that is, above 1.5 T. The new compounds are trimeric rigid structures that have slowly rotating bonds and, in addition, exhibit high speeds of aqueous sharing.

US-A1-2004 / 0265236 discloses trimeric macrocyclic substituted benzene derivatives that contain free rotation bonds. In particular, in the side chains of these compounds there is one or more than one methylene group, which allows these compounds to rotate freely. Trimeric macrocyclic substituted benzene derivatives have reduced relaxation compared to the compounds of the present invention due to the presence of free-rotation bonds.

Currently, the inventors have developed contrast agents with high relaxability for use in MR imaging and MR spectroscopy, which, in particular, perform at high magnetic field strengths, for example, at field strengths of 1.5 T, 3 T or higher.

Thus, according to a first aspect of the invention, there are provided compounds of formula (I) consisting of a core and —R — L — X groups attached to said core,

,

,

Where

A means hard core;

R are present or absent, and if present, are the same or different, and R means a moiety that is an obstacle to the rotation of the covalent bond between the core A and R and / or the covalent bond between R and L and / or L and X, if L is present, and / or a covalent bond between R and X, if L is absent;

L are present or absent, and, if present, are the same or different, and L means a linker group;

X are the same or different, and X means a chelator; and n is an integer of 3 or 4.

The term "chelator" means a chemical unit that binds (complexes) a metal ion to form a chelate. If the metal ion is a paramagnetic metal ion, then a chemical unit, that is, a complex formed by said paramagnetic metal ion and said chelator, is referred to as a “paramagnetic chelate”.

A preferred embodiment of a compound of formula (I) is a compound of formula (II) consisting of a core and —R — L — X ′ groups attached to said core,

,

,

where A means a hard core;

R are the same or different, and R means a group that is an obstacle to the rotation of the covalent bond between the core of A and R and / or the covalent bond between R and L and / or L and X, if L is present, and / or the covalent bond between R and X 'if L is absent;

L are present or absent, and, if present, are the same or different, and L means a linker group;

X 'are the same or different, and X' means a paramagnetic chelate consisting of a chelator X and a paramagnetic metal ion M; and

n is an integer of 3 or 4.

In said preferred embodiment, said paramagnetic chelate X 'consists of a chelator X and a paramagnetic metal ion M, said chelator X and paramagnetic metal ion M forming a complex, which is referred to as a paramagnetic chelate.

Hereinafter, the term "... X / X '", for example in R-L-X / X' or in the formulas, means that the formulated formula or the drawn formula are equally suitable for compounds or residues containing chelator X or paramagnetic chelate X '.

The compounds of formulas (I) and (II) are rigid compounds since they contain a rigid core A. Various molecules are known in organic chemistry that can satisfy this criterion. Preferably, A is a non-polymeric rigid core. In a further preferred embodiment, A represents a cyclic nucleus or carbon atom with 3 or 4 RLX / X 'groups attached, where if 3 RL-X / X' groups are attached to said carbon atom, then the fourth valency may be occupied by hydrogen or a group, selected from amino, hydroxyl, C ₁ -C ₃ alkyl or halogen.

In one embodiment, A is preferably a saturated or unsaturated, aromatic or aliphatic ring containing at least 3 carbon atoms and optionally one or more N, S or O heteroatoms, said ring being optionally substituted with one or more of the following substituents : C ₁ -C ₃ alkyl, possibly substituted with hydroxyl or amino groups, amino or hydroxyl groups or halogen, provided that n attachment points are left for RLX / X 'groups. Preferably, A is an aliphatic saturated or unsaturated 3-10 membered ring, such as cyclopropane, cyclobutane, cycloheptane or cyclohexane, which optionally contains one or more heteroatoms N, S or O, and which is optionally substituted with one or more substituents, representing C ₁ -C ₃ alkyl optionally substituted by hydroxyl or amino groups, amino or hydroxyl groups or halogen, provided that 3 or 4 attachment points are left for the RLX / X 'side groups. Alternatively, A is an aliphatic 3-10 membered ring, optionally containing one or more N, S or O heteroatoms, where one or more of one of the ring carbon atoms is a carbonyl group.

In another preferred embodiment, A is an aromatic single or fused 5-10 membered ring, optionally containing one or more N, S or O heteroatoms. Examples of such rings are, for example, benzene or naphthalene. The above rings are optionally substituted with one or more substituents, which are C ₁ -C ₃ -alkyl, optionally substituted with hydroxyl or amino groups, amino or hydroxyl groups or halogen, provided that 3 or 3 are left for the side groups RL-X / X ' 4 connection points

In addition, the compounds of formula (I) and (II) are rigid compounds, since the RLX / X 'side groups of formula (I) and (II) affect the restriction of the rotation of the covalent bond between the core A and R and / or the covalent bond between R and L and / or L and X / X 'if L is present, and / or a covalent bond between R and X / X' if L is absent, so that these bonds rotate preferably less than 10 ⁷ times per second at 37 ° FROM.

In the compounds of formulas (I) and (II), R are the same or different, and R means a moiety which is an obstacle to the rotation of covalent bonds between the core A and R and / or the covalent bond between R and L and / or L and X / X 'if L is present, and / or a covalent bond between R and X / X' if L is absent. This can be achieved in various ways, for example, a) by selecting a group R, which is a slowly rotating group, or b) by selecting a group R that rotation is hindered by steric interaction with the core and / or L, if L is present, and / or X / X ', and / or other R. groups

Regarding a), the term “slowly rotating grouping” means a grouping with a conformation lifetime of more than 0.1 μs. Preferred slowly rotating moieties and thus preferred R are substituted aromatic amides, such as N-methylanilides.

As for b), such steric interaction occurs when R is a bulky group similar to at least a 5-membered carbocyclic or heterocyclic ring, or a bicyclic or polycyclic ring. The use of a bulky group R, such as the aforementioned bulky groups, which is substituted with C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, can further facilitate this steric interaction. Such volumetric groupings R make rotation of the group R difficult due to interaction with one or more than one group R and / or T, and / or X / X ', and / or L, if present.

In a preferred embodiment, R is selected from the residue of an optionally substituted aromatic or non-aromatic 5-7 membered carbocyclic or heterocyclic ring, such as pyridinyl, phenyl, substituted phenyl, such as benzyl, ethylbenzyl or cyclohexyl. In another preferred embodiment, R is selected from the residue of a possibly substituted bicyclic or polycyclic ring, such as naphthyl or benzimidazolyl. Possible substituents are C ₁ -C ₈ alkyl, hydroxyl, amino or mercapto groups, or C ₁ -C ₈ alkyl containing one or more hydroxyl or amino groups, such as CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ , and / or an oxo group, such as CH ₂ OCH ₃ or OC ₂ H ₄ OH.

Since R joins A and L, if L is present, or X / X 'if L is absent, then the term "residues ..." is selected in the previous paragraph. Therefore, R should be considered as a residue.

In a particularly preferred embodiment, R is a residue of a substituted 6-membered aromatic ring, preferably a residue of a 6-membered aromatic ring containing a methyl or ethyl group.

R is attached to the core A either through a covalent bond or through covalent bonds. The former means a single covalent bond, while the latter reflects a situation where R is attached to the core A via more than one single covalent bond. This is the case when R is a cyclic moiety that has two points of attachment to core A, that is, which is fused to core A. This case is illustrated by formula IIIa, where A is a phenyl core having 3 R attached to it (bold ) in the form of condensed rings:

.

.

Alternatively, R is attached to A by a group of formula (IIIb):

,

,

Where

R ^b means H, C ₁ -C ₈ -alkyl, optionally substituted with one or more hydroxyl or amino groups.

Preferably, R ^b is H, C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, optionally substituted with one or more hydroxyl or amino groups, for example CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ or C ₂ H ₄ NH ₂ .

In the formula (IIIb), either a nitrogen atom or a carbonyl group can be attached to the core A. Preferably, a carbonyl group is attached to core A.

In another preferred embodiment, all R are the same.

In the compounds of formula (I) and (II), L may or may not be present. If L is absent, then R is directly bonded to X (compounds of formula (I)) or X '(compounds of formula (II)) via a covalent bond. If L is present, then L are the same or different, and each L means a linker moiety, that is, a moiety that is capable of linking A and X / X 'and R and X / X', respectively.

Preferred examples of L are:

Linker groups - (CZ ¹ Z ² ) _m -,

Where

m is an integer from 1 to 6; and

Z ¹ and Z ² independently from each other mean a hydrogen atom, a hydroxyl group or a C ₁ -C ₈ -alkyl group, possibly substituted by hydroxyl, amino or mercapto groups, for example CH ₂ OH and CH ₂ CH ₂ NH ₂ , and / or possibly containing an oxo group, for example CH ₂ OCH ₃ and OCH ₂ CH ₂ OH.

In the linker moieties —CZ ¹ Z ² —CO — N (R ^b ) - *, which are more preferred linker moieties,

* means the attachment of R to the specified linker group; and

Z ¹ , Z ² and R ^b have the meaning indicated above.

In a preferred embodiment, Z ¹ and Z ² are hydrogen, or Z ¹ is hydrogen, and Z ² is methyl, and R ^b is H, C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, optionally substituted with one or more hydroxyl or amino groups, for example CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ or C ₂ H ₄ NH ₂ .

Linker groups * -CO-N (R ^b ) - *,

Where

* means the addition of R to said linker moiety, that is, R is attached either to a carbon atom or to a nitrogen atom of said linker moiety; and

R ^b has the meaning indicated above.

Linker groups —CO — CZ ¹ Z ² —N (R ^b ) - *,

Where

* means the attachment of R to the specified linker group; and

Z ¹ , Z ² and R ^b have the meaning indicated above.

In a preferred embodiment, Z ¹ and Z ² are hydrogen, or Z ¹ is hydrogen, and Z ² is methyl, and R ^b is H, C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, optionally substituted with one or more hydroxyl or amino groups, for example CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ or C ₂ H ₄ NH ₂ .

Linker moieties representing the amino acid residues —CH ₂ —CO — NH — CH (Z ³ ) CO — NH— *,

where * means the attachment of R to the specified linker group; and

Z ³ means a side group of natural α-amino acids.

Further preferred examples of L are or contain residues of benzene or N-heterocycles, such as imidazoles, triazoles, pyrazinones, pyrimidines and piperidines, where R is attached to one of the nitrogen atoms in said N-heterocycles or to the carbon atom in said heterocycles or in benzene .

If L contains one of the above residues, i.e. benzene or an N-heterocycle, then L is preferably

- * N-heterocycle- (CZ ¹ Z ² ) _m - or - * benzene- (CZ ¹ Z ² ) _m -,

where R is attached to one of the nitrogen atoms in the specified N-heterocycle or to the carbon atom in the specified benzene; and

Z ¹ , Z ² and m are as defined above.

Preferred examples of such linker moieties are:

,

,

where * means the addition of R to the specified linker group, # means the addition of X / X 'to the specified linker group, and m is 1 or 2.

Preferably, if L are present, then all L are the same.

In the compounds of formula (I), X are the same or different, and X is a chelator. In a preferred embodiment of the compounds of formula (II), X is X ′, which means a paramagnetic chelate, that is, a chelator X, complexing with the paramagnetic metal ion M. Numerous chelators are known in the art which complex with the paramagnetic metal ions M. Preferably X is a cyclic chelator of formula (IV):

,

,

Where

* means joining L if L is present, or to the core if L is absent;

E ₁ -E _{4 are} independently selected from H, CH ₂ , CH ₃ , OCH ₃ , CH ₂ OH, CH ₂ OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ OH, COOH, COOCH ₃ , COOCH ₂ CH ₃ , C (O) NH ₂ , C (O) N (CH ₃ ) ₂ , C (O) N (CH ₂ CH ₃ ) CH ₃ or C (O) N (CH ₂ CH ₃ ) ₂ ;

G ₁ -G _{4 are} independently selected from H, CH ₂ , CH ₃ , OCH ₃ , CH ₂ OH, CH ₂ OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ OH, COOH, COOCH ₃ , COOCH ₂ CH ₃ , C (O) NH ₂ , C (O) N (CH ₃ ) ₂ , C (O) N (CH ₂ CH ₃ ) CH ₃ or C (O) N (CH ₂ CH ₃ ) ₂ ;

D ₁ -D _{3 are} independently selected from H, OH, CH ₃ , CH ₂ CH ₃ , CH ₂ OH, CH ₂ OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ OH, or OCH ₂ C ₆ H ₅ ; and

J ₁ -J _{3 are} independently selected from COOH, P (O) (OH) ₂ , P (O) (OH) CH ₃ , P (O) (OH) CH ₂ CH ₃ , P (O) (OH ) (CH ₂ ) ₃ CH ₃ , P (O) (OH) Ph, P (O) (OH) CH ₂ Ph, P (O) (OH) OCH ₂ CH ₃ , CH (OH) CH ₃ , CH ( OH) CH ₂ OH, C (O) NH ₂ , C (O) NHCH ₃ , C (O) NH (CH ₂ ) ₂ CH ₃ , OH or H.

Preferred chelators X are diethylenetriaminopentaacetic acid (DTPA) residues, N- [2- [bis (carboxymethyl) amino] -3- (4-ethoxyphenyl) propyl] -N- [2- [bis (carboxymethyl) amino] ethyl] -L-glycine (EOB-DTPA), N, N-bis [2- [bis (carboxymethyl) amino] ethyl] -L-glutamic acid (DTPA-Glu), N, N-bis [2- [bis ( carboxymethyl) amino] ethyl] -L-lysine (DTPA-Lys), mono- or bis-amide derivatives of DTPA, for example N, N-bis [2- [carboxymethyl [(methylcarbamoyl) methyl] amino] ethyl] glycine (DTPA-BMA), 4-carboxy-5,8,11-tris (carboxymethyl) -1-phenyl-2-oxa-5,8,11-triazatridecane-13-oic acid (BORTA), DTPA BORTA, 1, 4,7,10- tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), 10- (2-hydroxypropyl ) -1,4,7,10-tetraazacyclodecane-1,4,7-triacetic acid (HPDO3A), 2-methyl-1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (MCTA) ), tetramethyl-1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTMA), 3,6,9,15-tetraazabicyclo [9.3.1] pentadeca-1 (15), 11 , 13-triene-3,6,9-triacetic acid (PCTA), PCTA12, cyclo-PCTA12, N, N'-bis (2-aminoethyl) -1,2-ethanediamine (TETA), 1,4,7, 10-tetraazacyclotridecan-N, N ', N' ', N' '' - tetrauxus acid (TRITA), 1,12-dicarbonyl, 15- (4-isothiocyanatobenzyl) -1,4,7,10,13-pentaazacyclohexadecane-N, N ', N' '- triacetic acid (НЕТА), mono- ( 1,4,7,10-tetraazacyclododecane-N, N ′, N ″, N ″ ″ - tetraacetic acid N-hydroxysuccinimididyl ester), tetraacetic acid (DOTA-NHS), N, N'-bis (2- aminoethyl) -1,2-ethanediamine (TETA-NHS), [(2S, 5S, 8S, 11S) -4,7,10-tris-carboxymethyl-2,5,8,11-tetramethyl-1,4,7 , 10-tetraazacyclododecan-1-yl] acetic acid (M4DOTA), [(2S, 5S, 8S, 11S) -4,7-bis-carboxymethyl-2,5,8,11-tetramethyl-1,4,7, 10-tetraazacyclo-dodecan-1-yl] -acetic acid, (M4DO3A), (R) -2 - [(2S, 5S, 8S, 11S) -4,7,10-tris - ((R) -1-carboxyethyl ) -2,5,8,11-t tramethyl-1,4,7,10-tetraazacyclododecan-1-yl] propionic acid (M4DOTMA), 1-O-phosphonomethyl-1,4,7,1-O-tetraazacyclododecane-1,4,7-triacetic acid (MPDO3A ), hydroxybenzyl-ethylenediamine-diacetic acid (HBED) and N, N'-ethylenebis- [2- (o-hydroxyphenol) glycine] (EHPG).

Since the chelator is attached to the remainder of the molecule representing the compounds of formula (I) and (II), the term "residues ..." is selected in the previous paragraph; therefore, R should be considered as a residue. The attachment point of X to the indicated residue of the molecule representing the compounds of formula (I) and (II) can be any suitable point, for example a functional group, such as a COOH group in a chelator like DTPA, EDTA or DOTA, or an amino group in chelators like DTPA- Lys, as well as a non-functional group similar to the methylene group in chelators like DOTA.

Suitable chelators X and their syntheses are described, for example, in EP-A-071564, EP-A-448191, WO-A-02/48119, US 6399043, WO-A-01/51095, EP-A-203962, EP- A-292689, EP-A-425571, EP-A-230893, EP-A-405704, EP-A-290047, US 6123920, US-A-2002/0090342, US 6403055, WO-A-02/40060, US 6458337, US 6264914, US 6221334, WO-A-95/31444, US 5573752, US 5358704 and US-A-2002/0127181, the contents of which are incorporated herein by reference.

In a more preferred embodiment of the present invention, X is selected from DOTA, DTPA, BOPTA, DO3A, HPDO3A, MCA, DOTMA, DTPA BMA, M4DOTA, M4DO3A, PCTA, TETA, TRITA, HETA, DPDP, EDTA or EDTP residues.

In a particularly preferred embodiment, X is selected from the residues of DTPA, DOTA, BOPTA, DO3A, HPDO3A, DOTMA, PCTA, DTPA BMA, M4DOTA or M4DO3A.

As described above, in a preferred embodiment X, that is X ′, the chelator X forms a complex, that is, a paramagnetic chelate, with a paramagnetic metal ion M. Suitable M is a paramagnetic ion of a transition metal or lanthanide metal, i.e., metals with atomic numbers 21- 29, 42, 43, 44 or 57-71. More preferably, M is a paramagnetic ion of Mn, Fe, Co, Ni, Eu, Gd, Dy, Tm and Yb, particularly preferably a paramagnetic ion of Mn, Fe, Eu, Gd and Dy. Most preferably, M is selected from Gd ³⁺ , Mn ²⁺ , Fe ³⁺ , Dy ³⁺ and Eu ³⁺ , with Gd ³⁺ being the most preferred paramagnetic ion M.

When modeling or simulating the behavior of compounds of formula (I) or (II) using theoretical methods and computational techniques (molecular modeling), in a preferred embodiment, these compounds can be inscribed in a sphere with a diameter of from 2 to 3.5 nm, preferably in a sphere with diameters from 2 to 2.5 nm, using molecular modeling software, which is based on MM3 theoretical force field methods (for example, Spartan software), and these compounds are simulated in vacuum.

Preferred compounds of formula (I) and (II), where n is 3, are compounds of formula (V) and (VI) consisting of a cyanuric acid core and —R — L — X groups attached to said core:

,

,

where R, L, X and X 'are as defined above, and all R, L, X and X' are the same.

In a preferred embodiment of the compounds of formulas (V) and (VI), R is a residue of a possibly substituted aromatic or non-aromatic 5-7 membered carbocyclic or heterocyclic ring, such as pyridinyl, phenyl, substituted phenyl, such as benzyl, ethylbenzyl or cyclohexyl. In another preferred embodiment, R is selected from the residue of a possibly substituted bicyclic or polycyclic ring, such as naphthyl or benzimidazolyl. Possible substituents are C ₁ -C ₈ alkyl, hydroxyl, amino or mercapto groups, or C ₁ -C ₈ alkyl containing one or more hydroxyl or amino groups, such as CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ , and / or an oxo group, such as CH ₂ OCH ₃ or OC ₂ H ₄ OH.

In a more preferred embodiment, R is a residue of a substituted 6-membered aromatic ring, for example benzyl, or, preferably, a residue of a 6-membered aromatic ring containing a methyl or ethyl group, such as benzyl or ethyl phenyl.

In a preferred embodiment of the compounds of formula (V) and (VI), L represents a linker moiety —CZ ¹ Z ² —CO — N (R ^b ) - *,

Where

* means the attachment of R to the specified linker group; and

Z ¹ , Z ² and R ^b have the meaning indicated above.

In a preferred embodiment, Z ¹ and Z ² are hydrogen, or Z ¹ is hydrogen, and Z ² is methyl, and R ^b is H, C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, optionally substituted with one or more hydroxyl or amino groups, for example CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ or C ₂ H ₄ NH ₂ .

In another preferred embodiment, L is the remainder of N-heterocycles, such as imidazole, triazole, pyrazinone, pyrimidine and piperidine, where R is attached to one of the nitrogen atoms in the specified N-heterocycle.

In another preferred embodiment, L represents one of the following linker groups:

,

,

where * means the addition of R to the specified linker group, # means the addition of X / X 'to the specified linker group, and m is 1 or 2.

In a preferred embodiment of the compounds of formula (V) and (VI), X is selected from DOTA, DTPA, BOPTA, DO3A, HPDO3A, MCTA, DOTMA, DTPA BMA, M4DOTA, M4DO3A, PCTA, TETA, TRITA, HETA, DPDP, EDTA or EDTP residues .

More preferably, X is selected from DTPA, DOTA, BOPTA, DO3A, HPDO3A, DOTMA, PCTA, DTPA BMA, M4DOTA or M4DO3A residues. In a most preferred embodiment, X is a chelator of formula (IV).

In a preferred embodiment of the compounds of formula (VI), M is selected from Gd ³⁺ , Mn ²⁺ , Fe ³⁺ , Dy ³⁺ and Eu ³⁺ , with Gd ³⁺ being the most preferred paramagnetic ion M.

In a preferred embodiment of the compounds of formula (V) and (VI), all R are the same, all L are the same, all X are the same, and all X 'are the same.

Other preferred compounds of formula (I) and (II), where n is 3, are compounds of formula (VII) and (VIII) consisting of a phenyl core (substituted if T is not hydrogen) and -RLX groups attached to the specified core :

,

,

Where

R, L, X and X 'are as defined above; and

T are the same or different, and T means a single atom or a small group.

If T is a small group, then it preferably is a small organic group having a molecular weight of less than 100 Da. In a more preferred embodiment, T is selected from C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, optionally substituted with one or more hydroxyl or amino groups, for example CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ or C ₂ H ₄ NH ₂ . If T is a single atom, then it is preferably selected from H, F or Cl.

In another preferred embodiment, all T are the same.

In a preferred embodiment of the compounds of formula (VII) and (VIII), R is a residue of an optionally substituted aromatic or non-aromatic 5-7 membered carbocyclic or heterocyclic ring, such as pyridinyl, phenyl, substituted phenyl, such as benzyl, ethylbenzyl or cyclohexyl. In another preferred embodiment, R is selected from the residue of a possibly substituted bicyclic or polycyclic ring, such as naphthyl or benzimidazolyl. Possible substituents are C ₁ -C ₈ alkyl, hydroxyl, amino or mercapto groups, or C ₁ -C ₈ alkyl containing one or more hydroxyl or amino groups, such as CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ , and / or an oxo group, such as CH ₂ OCH ₃ or OC ₂ H ₄ OH.

In a more preferred embodiment, R is a residue of a substituted 6-membered aromatic ring, for example benzyl, or a residue of a 6-membered aromatic ring containing a methyl or ethyl group, such as benzyl or ethyl phenyl.

In another preferred embodiment, R is attached to the substituted phenyl core by a moiety of formula (IIIb):

,

,

Where

R ^b is H, C ₁ -C ₈ alkyl optionally substituted with one or more hydroxyl or amino groups, preferably H or C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, more preferably methyl.

In a preferred embodiment of the compounds of formula (VII) and (VIII), L is a linker moiety

-CZ ¹ Z ² -CO-N (R ^b ) - *,

Where

* means the attachment of R to the specified linker group; and

Z ¹ , Z ² and R ^b have the meaning indicated above.

In a preferred embodiment, Z ¹ and Z ² are hydrogen, or Z ¹ is hydrogen, and Z ² is methyl, and R ^b is H, C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, optionally substituted with one or more hydroxyl or amino groups, for example, CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ or C ₂ H ₄ NH ₂ .

In a preferred embodiment of the compounds of formula (VII) and (VIII), X is selected from DOTA, DTPA, BOPTA, DO3A, HPDO3A, MCTA, DOTMA, DTPA BMA, M4DOTA, M4DO3A, PCTA, TETA, TRITA, HETA, DPDP, EDTA or EDTP residues .

More preferably, X is selected from DTPA, DOTA, BOPTA, DO3A, HPDO3A, DOTMA, PCTA, DTPA BMA, M4DOTA or M4DO3A residues. In a most preferred embodiment, X is a chelator of formula (IV).

In a preferred embodiment of the compounds of formula (VIII), M is selected from Gd ³⁺ , Mn ²⁺ , Fe ³⁺ , Dy ³⁺ and Eu ³⁺ , with Gd ³⁺ being the most preferred paramagnetic ion M.

In a preferred embodiment of the compounds of formula (VII) and (VIII), all T are the same, all R are the same, all L are the same, all X are the same, and all X 'are the same.

Other preferred compounds of formula (I) and (II), where n is 3, are compounds of formula (IX) and (X), consisting of a phenyl core and RLX groups attached to the specified phenyl core, where R is a cyclic condensed moiety with the indicated phenyl core, and the LX groups are attached to R at the 1st carbon atom or at the 2nd carbon atom

,

,

Where

Qa are the same or different, and Qa means C (Rc) ₂ , CH ₂ S, S, SO, SO ₂ or NRc, where Rc is selected from hydrogen or lower alkyl, preferably C ₁ -C ₃ alkyl, for example methyl, ethyl , n-propyl or isopropyl, optionally substituted with one or more hydroxyls or groups, or optionally containing one or more hydroxy groups, for example CH ₂ OH, C ₂ H ₄ OH, CH ₂ OCH ₃ or C ₂ H ₄ OCH ₃ ;

L may be present or absent, and, if present, may be the same or different, and L means a linker group; and

X and X 'are as defined above.

In a preferred embodiment, Qa are the same, and Qa preferably means C (Rc) ₂ , where Rc is preferably selected from hydrogen or lower alkyl, preferably C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, optionally substituted with one or more hydroxyls or groups, or optionally containing one or more hydroxy groups, for example CH ₂ OH, C ₂ H ₄ OH, CH ₂ OCH ₃ or C ₂ H ₄ OCH ₃ .

In a preferred embodiment of the compounds of formula (IX) and (X), L is a linker moiety —CZ ¹ Z ² —CO — N (R ^b ) - *,

Where

* means the attachment of the nucleus to the specified linker group; and

Z ¹ , Z ² and R ^b have the meaning indicated above.

In a preferred embodiment, Z ¹ and Z ² are hydrogen, or Z ¹ is hydrogen, and Z ² is methyl, and R ^b is H, C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, optionally substituted with one or more hydroxyl or amino groups, for example CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ or C ₂ H ₄ NH ₂ .

In a preferred embodiment of the compounds of formula (IX) and (X), X is selected from DOTA, DTPA, BOPTA, DO3A, HPDO3A, MCTA, DOTMA, DTPA BMA, M4DOTA, M4DO3A, PCTA, TETA, TRITA, HETA, DPDP, EDTA or EDTP residues .

More preferably, X is selected from DTPA, DOTA, BOPTA, DO3A, HPDO3A, DOTMA, PCTA, DTPA BMA, M4DOTA or M4DO3A residues. In a most preferred embodiment, X is a chelator of formula (IV).

In a preferred embodiment of the compounds of formula (X), M is selected from Gd ³⁺ , Mn ²⁺ , Fe ³⁺ , Dy ³⁺ and Eu ³⁺ , with Gd ³⁺ being the most preferred paramagnetic ion M.

In a preferred embodiment of the compounds of formula (IX) and (X), all L are the same, all X are the same, and all X 'are the same.

Other preferred compounds of formula (I) and (II) are compounds of formula (XI) and (XII), consisting of a nucleus of carbon atoms, having n benzene residues R attached to the specified nucleus of carbon atoms, and n groups-LX attached to R

,

,

where L, X, X 'and n are as defined above.

If n is 3, then the fourth valency is preferably occupied by hydrogen or a group selected from amino, hydroxyl, C ₁ -C ₃ alkyl or halogen, more preferably hydrogen or hydroxyl.

In a preferred embodiment of the compounds of formula (XI) and (XII), L is a linker moiety

-CZ ¹ Z ² -CO-N (R ^b ) - *,

Where

* means the attachment of R to the specified linker group; and

Z ¹ , Z ² and R ^b have the meaning indicated above.

In a preferred embodiment, Z ¹ and Z ² are hydrogen, or Z ¹ is hydrogen, and Z ² is methyl, and R ^b is H, C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, optionally substituted with one or more hydroxyl or amino groups, for example CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ or C ₂ H ₄ NH ₂ .

In a preferred embodiment of the compounds of formula (XI) and (XII), X is selected from DOTA, DTPA, BOPTA, DO3A, HPDO3A, MCTA, DOTMA, DTPA BMA, M4DOTA, M4DO3A, PCTA, TETA, TRITA, HETA, DPDP, EDTA or EDTP residues .

More preferably, X is selected from residues DTPA, DOTA, BOPTA, DO3A, HPDO3A, DOTMA, PCTA, DTPA BMA, M4DOTA or M4DO3A. In a most preferred embodiment, X is a chelator of formula (IV).

In a preferred embodiment of the compounds of formula (XII), M is selected from Gd ³⁺ , Mn ²⁺ , Fe ³⁺ , Dy ³⁺ and Eu ³⁺ , with Gd ³⁺ being the most preferred paramagnetic ion M.

In a preferred embodiment of the compounds of formula (XI) and (XII), all L are the same, all X are the same, and all X 'are the same.

Other preferred compounds of formula (I) and (II), where n is 3, are compounds of formula (XIII) and (XIV) consisting of a cyclohexyl core substituted with hydroxyl and R-L-X groups attached thereto.

,

,

where R, L and X are as defined above.

In a preferred embodiment of the compounds of formula (XIII) and (XIV), R represents a residue of a possibly substituted aromatic or non-aromatic 5-7 membered carbocyclic or heterocyclic ring, such as pyridinyl, phenyl, substituted phenyl, such as benzyl, ethylbenzyl or cyclohexyl. In another preferred embodiment, R is selected from the residue of a possibly substituted bicyclic or polycyclic ring, such as naphthyl or benzimidazolyl. Possible substituents are C ₁ -C ₈ alkyl, hydroxyl, amino or mercapto groups, or C ₁ -C ₈ alkyl containing one or more hydroxyl or amino groups, such as CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ , and / or an oxo group, such as CH ₂ OCH ₃ or OC ₂ H ₄ OH.

In a more preferred embodiment, R is a residue of a substituted 6-membered aromatic ring, for example benzyl, or a residue of a 6-membered aromatic ring containing a methyl or ethyl group, such as benzyl or ethyl phenyl.

In another preferred embodiment, R is attached to a substituted cyclohexyl ring by a moiety of formula (IIIb):

,

,

Where

R ^b is H, C ₁ -C ₈ alkyl optionally substituted with one or more hydroxyl or amino groups, preferably H or C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, more preferably methyl.

In a preferred embodiment of the compounds of formula (XIII) and (XIV), L is a linker moiety

-CZ ¹ Z ² -CO-N (R ^b ) - *,

Where

* means the attachment of R to the specified linker group; and

Z ¹ , Z ² and R ^b have the meaning indicated above.

In a preferred embodiment, Z ¹ and Z ² are hydrogen, or Z ¹ is hydrogen, and Z ² is methyl, and R ^b is H, C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, optionally substituted with one or more hydroxyl or amino groups, for example CH ₂ OH, C ₂ H ₄ OH, CH ₂ NH ₂ or C ₂ H ₄ NH ₂ .

In a preferred embodiment of the compounds of formula (XIII) and (XIV), X is selected from DOTA, DTPA, BOPTA, DO3A, HPDO3A, MCTA, DOTMA, DTPA BMA, M4DOTA, M4DO3A, PCTA, TETA, TRITA, HETA, DPDP, EDTA or EDTP residues .

More preferably, X is selected from DTPA, DOTA, BOPTA, DO3A, HPDO3A, DOTMA, PCTA, DTPA BMA, M4DOTA or M4DO3A residues. In a most preferred embodiment, X is a chelator of formula (IV).

In a preferred embodiment of the compounds of formula (XIV), M is selected from Gd ³⁺ , Mn ²⁺ , Fe ³⁺ , Dy ³⁺ and Eu ³⁺ , with Gd ³⁺ being the most preferred paramagnetic ion M.

In a preferred embodiment of the compounds of formula (XIII) and (XIV), all R are the same, all L are the same, all X are the same, and all X 'are the same.

Compounds of formula (I) and (II) can be synthesized from commercially available starting materials by several synthetic routes known to one skilled in the art.

Basically, two possible paths are considered: path 1 is based on building blocks and stepwise synthesis, while path 2 is based on the polymerization of an appropriately substituted monomer followed by stepwise synthesis.

For the 1st path, the core is used as the first building block, where the specified core is replaced by n reactive groups involving the addition of R. Alternatively, for compounds of formula (IX) and (X) and compounds of formula (XI) and (XII), the first the building block is composed of a core and R groups condensed with the specified core or attached to the specified core, and is replaced by 3 reactive groups involving the addition of L. Examples of reactive groups are, for example, groups with activated acid func a group, for example, an acid chloride group or amino groups, and methods for introducing these reactive groups of said first building block are known in the art. R / L or the R / L precursor is reacted with a substituted first building block to form a second building block consisting of a core and R or a core, R and L. To carry out this reaction, R / L contain reactive groups that are able to interact with reactive groups of the first building block, reaching the accession of R / L to the specified first building block. If the compounds of formula (I) or (II) contain a linker group L, then the specified linker group is replaced by a reactive group involving joining R in the second building block. Similarly, R contains a reactive group that is capable of interacting with L or the precursor of L to allow the addition of L to form a third building block. In the next step, X or X ′ or a precursor thereof is attached to the third building block or second building block in the case of compounds of formula (IX) and (X) to form compounds of formula (I) or (II). If X and / or X 'contain reactive groups such as COOH, then protection of these groups may be required; and suitable protecting groups are known in the art. Alternatively, X or a precursor thereof is attached to said second or third building block to form compounds of formula (I), which are then converted to compounds of formula (II) in the next step, including optional deprotection of X, if used in a protected form, and complexation with a suitable paramagnetic metal ion M, preferably in the form of its salt (for example, such as Gd (III) acetate or Ga (III) Cl ₃ acetate).

In another embodiment, a building block is made up of LX or LX 'or a precursor thereof, which is then reacted with a second building block or first building block in the case of compounds of formula (IX) and (X), as described above, to form compounds of formula ( I) or (II). Again, if X and / or X 'contain reactive groups such as COOH, then protection of these groups may be required; and suitable protecting groups are known in the art. Alternatively, X or a precursor thereof is attached to said second building block to form compounds of formula (I), which are then converted to compounds of formula (II) in the next step, including optional deprotection of X, if used in a protected form, and complexation with a suitable a paramagnetic metal ion M, preferably in the form of a salt thereof (for example, such as Gd (III) acetate or Gd (III) Cl ₃ acetate).

Thus, another aspect of the invention is a method for producing compounds of formula (I), including

a) the use as the first building block of core A, which is substituted by reactive groups involving the addition of R;

b) the interaction of R or its predecessor with the specified first building block with the formation of the second building block, consisting of a core A and R;

c) possibly the interaction of L or its predecessor with the specified second building block with the formation of the third building block, consisting of a core A, R and L; and

d) the interaction of X or its predecessor with the specified second or third building block.

Another aspect of the invention is a method for producing compounds of formula (I), including

a) the use as the first building block of core A, which is substituted by reactive groups involving the addition of R;

b) the interaction of R or its predecessor with the specified first building block with the formation of the second building block, consisting of a core A and R; and

c) the interaction of the building block, consisting of L-X or its predecessor, with the specified second building block.

Another aspect of the invention is a method for producing compounds of formula (I), including

a) the use of the first building block, consisting of a core A and R, condensed with A or attached to A, where R is substituted by reactive groups involving the addition of L or X;

b) it is possible that L or its predecessor interacts with said first building block to form a second building block consisting of core A, R and L; and

c) the interaction of X or its predecessor with the specified first or second building block.

Another aspect of the invention is a method for producing compounds of formula (I), including

a) the use of the first building block, consisting of a core A and R, condensed with A or attached to A, where R is substituted by reactive groups involving the addition of L and;

b) the interaction of the building block, consisting of L-X or its predecessor, with the specified first building block.

The methods of the invention are suitable for the preparation of compounds of formula (II) if, at a subsequent stage, complexation occurs with a suitable paramagnetic metal ion M, preferably in the form of a salt thereof (for example, acetate Gd (III) or Gd (III) Cl ₃ ).

For the 2nd pathway, a suitably substituted monomer is polymerized, i.e., a trimer (n is 3) or an intermediate in the form of a tetramer (n is 4) is synthesized from the indicated monomer by trimerization or tetramerisation, and the polymerization is carried out by stepwise synthesis. A suitable monomer contains a moiety which, after polymerization, forms A. In addition, the monomer contains R containing a reactive moiety or a precursor thereof, comprising attaching L or its precursor, if L is present, or X / X ′ or its precursor. An example of such a reactive group can be an amino group, and its precursor can be a nitro group, which in itself is not reactive, that is, the nitro group will not take part in the polymerization reaction. After polymerization, the nitro group can be reduced to a reactive amino group. Other reactive groups or a precursor thereof, for example a carboxyl group and an ester, as its possible precursor, are known in the art. After polymerization and the possible conversion of the precursor to a reactive group, L or the L precursor, if present in the final reaction product, is reacted with an intermediate obtained by tri- or tetramerisation of the monomer. In the next step, X or X ′ is added to form compounds of formula (I) or (II). If X and / or X 'contain reactive groups such as COOH, then protection of these groups may be required; and suitable protecting groups are known in the art. Alternatively, X is attached to form compounds of formula (I), which are then converted to compounds of formula (II) in the next step, including optional deprotection of X, if used in a protected form, and complexation with a suitable paramagnetic metal ion M, preferably in the form salts thereof (e.g., such as Gd (III) acetate or Gd (III) Cl ₃ acetate).

Thus, another aspect of the invention is a method for producing compounds of formula (I), including

a) trimerization or tetramerization of a monomer containing a group which, after trimerization or tetramerization, forms A, wherein said monomer further comprises R containing a reactive group or its precursor, providing for the addition of L or its precursor, if L is present, or X or its predecessor , with the formation of an intermediate compound;

b) possibly the interaction of L or its predecessor with the specified intermediate compound; and

c) the interaction of X or its precursor with the intermediate compound or reaction product of stage b).

The method according to the invention described above is suitable for the preparation of compounds of formula (II) if, in a subsequent step, complexation occurs with a suitable paramagnetic metal ion M, preferably in the form of a salt thereof (for example, acetate Gd (III) or Gd (III) Cl ₃ ).

The compounds of formula (V) and (VI) can be synthesized either by 1 or by 2, preferably by 2. The first step of said route 2 is the trimerization of 4-nitrophenyl isocyanate or a derivative thereof like 2-methyl-4-nitrophenyl isocyanate 1 to form an intermediate compound containing a cyanuric acid core and a benzene residue or a substituted benzene residue R, where R contains a nitro group (2, 1,3,5-tris- (4-nitro-2-methylphenyl) - [1,3,5] triazinan- 2,4,6-trion), which is the precursor of a reactive group (amino group), pre sees joining L or X / X '(3, 1,3,5-tris- (4-amino-2-methylphenyl) - [1,3,5] triazinan-2,4,6-trione).

Starting compound 1 can be prepared by reacting 2-methyl-4-nitroaniline with phosgene. The best yields are achieved by trimerization in an airtight vessel. Additionally, shorter reaction times and higher yield values can be achieved by hydrogenation in the process of obtaining 3 in a mixture of solvents of tetrahydrofuran (THF) and water.

Thus, according to another aspect of the invention, an improved method for producing 1,3,5-tris- (4-amino-2-methylphenyl) - [1,3,5] triazinan-2,4,6-trion) by trimerization of 2- methyl 4-nitrophenylisocyanate in an airtight vessel and hydrogenating the resulting trimer in a mixture of tetrahydrofuran and water solvents. Preferably, the hydrogenation is carried out using Pd / C as a catalyst.

The attachment of L to the amino groups of compound 3 can be carried out using methods known in the art. In a preferred embodiment, L is a linker moiety containing an N-heterocycle residue, preferably a triazole residue, a pyrazinone residue or an imidazole residue.

If L contains an imidazole residue, then intermediate 3 is preferably reacted with a tosylmethyl isocyanide reagent as described by J. Sisiko et al. in J. Org. Chem. 2000, 65, 1516-1524, to give 4:

Reaction product 4 contains mesylate groups that readily interact with X, for example tert-butyl-protected DO3A, to form a compound of formula (I), which in the next step can be converted to a compound of formula (II), wherein said next step involves the removal protection with X and complexation with a suitable paramagnetic metal ion M, preferably in the form of its salt (for example, acetate Gd (III) or Gd (III) Cl ₃ ).

If L contains a pyrazinone residue, then intermediate 3 is preferably reacted with a diketone and a serine derivative as described by Chuyen et al. in agr. Biol. Chem. 37 (2), 1973, 327-334, to give 5:

Reaction product 5 contains hydroxyl groups which can be easily converted to mesylate groups that react easily with X, for example tert-butyl-protected DO3A, to form a compound of formula (I), which in the next step can be converted to a compound of formula (II ), wherein said next step involves deprotecting X and complexing with a suitable paramagnetic metal ion M, preferably in the form of a salt thereof (for example, Gd (III) acetate or Gd (III) Cl ₃ acetate).

If L contains a triazole residue, then such a triazole ring is readily available due to the catalyzed Cu (I) cyclization of organic azide and terminal acetylene, as described by Vsevolod et al. at Angew Chem. Int. Ed. 2002, 41 (14), 1596-1599. However, the handling of organic azides, especially in large quantities, is difficult due to the possibility of their rapid decomposition. Therefore, in a preferred embodiment, intermediate 3 is converted to azide under standard diazotization conditions, followed by the addition of sodium azide using a single reactor. After completion of the reaction, the reaction mixture was neutralized and propargyl alcohol was added together with a source of Cu (I), obtaining 6:

Reaction product 6 contains hydroxyl groups which can be easily converted to mesylate groups that react easily with X, for example tert-butyl-protected DO3A, to form a compound of formula (I), which in the next step can be converted to a compound of formula (II ), wherein said next step involves deprotecting X and complexing with a suitable paramagnetic metal ion M, preferably in the form of a salt thereof (for example, Gd (III) acetate or Gd (III) Cl ₃ acetate).

The compounds of formula (VII) and (VIII) can be synthesized either by 1 or by 2. For the 1st pathway, the first step is the synthesis of the first building block, that is, a core substituted by 3 reactive groups involving the addition of R.

If T is hydrogen, then a commercially available compound, 1,3,5-benzene tricarboxylic acid (trimesinic acid), can be used as a starting compound. Trimesic acid can be converted to the acid chloride using methods known in the art, for example by reaction with PCl ₅ . The 1,3,5-benzenetricarboxylic acid chloride is the first building block and consists of an unsubstituted phenyl core substituted with three reactive groups, i.e., the acid chloride groups of the carboxylic acid. These groups can interact with R groups containing, for example, an amino group, and thus form a —CO — NH— group after reaction with the acid chloride groups of the carboxylic acid.

If T is C ₁ -C ₃ -alkyl, for example methyl, then the first building block can be synthesized using 1,3,5-tri-C ₁ -C ₃ -alkylbenzene as the starting compound, for example 1,3,5 -trimethylbenzene or 1,3,5-triisopropylbenzene, when carrying out the method as described in examples 4-7.

If T is halogen, for example Cl, then the first building block can be synthesized using 1,3,5-trimethylbenzene as the starting compound by converting the specified starting compound to 1,3,5-trimethyl-2,4,6-trichlorobenzene as described by K. Shoji et al. in Bull. Chem. Soc. Jpn. 62, 1989, 2096-2098. Subsequent oxidation leads to 2,4,6-trichlorobenzene-1,3,5-tricarboxylic acid, which can be converted to reactive acid chloride by reaction with thionyl chloride.

The first step of path 2 for the synthesis of compounds of formulas (VII) and (VIII) is the trimerization of R — C (O) CH ₃ monomer in the presence of trifluoromethanesulfonic acid, which leads to an intermediate product consisting of a phenyl core with R. substituents. An example of such a monomer is 4- acetamido-2-methylacetophenone, and trimerization of said monomer leads to intermediate 7,

,

,

consisting of a phenyl core and R being a toluene residue, where R is substituted with a reactive group —NH — CO — CH ₃ , which can be converted to a linker or linker precursor to which X / X ′ is attached. This synthesis is described in detail in example 2.

The compounds of formula (IX) and (X) can be synthesized either by way of 1 or by way of 2. According to the 2nd way, preferably those compounds of formula (IX) and (X) are synthesized, where Qa is CH ₂ or C (Rc) ₂ , where Rc is lower alkyl, optionally substituted with one or more hydroxyl groups or possibly containing one or more hydroxy groups, or where Qa is S, SO, or SO ₂ .

If Qa is CH ₂ or C (Rc) ₂ , where Rc is lower alkyl, optionally substituted with one or more hydroxyl groups or possibly containing one or more hydroxy groups, then the compounds of formula

(IX) or (X) can be easily synthesized by trimerization of acid-catalyzed 2-indanone or 1- (Rc) ₂ -2-indanone.

If Qa is S, then the compounds of formula (IX) or (X) can be synthesized by trimerization of 3 (2H) benzothiophenone, as described by Dagliesh et al. in J. Chem. Soc. 910 (1945) and Proetzsch et al. at Z. Naturforsch. 31B, 529 (1976).

If Qa is SO or SO ₂ , then the compounds of formula (IX) or (X) can be synthesized as described in the previous paragraph, and S can be oxidized using methods known in the art. Oxidation also increases the solubility of the intermediates obtained by said trimerization.

Since the trimerization of 3 (2H) benzothiophenone leads to poorly soluble intermediates, it is preferable to increase the solubility at an early stage of the synthesis. A possible way is shown in reaction scheme 1:

When choosing this approach, reactive groups, i.e. amino groups, are already introduced into the molecule, which can then be used to attach L or X, if L is absent, to the C-atom 1.

If Qa is NRc, then the compounds of formula (IX) and (X) can be synthesized by combining Ulman with N-substituted-2-iodoindole, for example 2-iodo-N-methylindole, if Rc is methyl, as described in Bergman et al. in Tetrahedron 36, 1439 (1980).

After completion of the synthesis of the intermediate, said intermediate is activated by introducing suitable reactive groups at the C-atom 1 or 2, depending on where the —L — X groups are to be attached. To activate the intermediate compound at the 1st C-atom, the intermediate compound is easily synthesized by trimerizing a compound already containing the indicated reactive groups, for example, by trimerizing a molecule containing a nitro group and reducing said nitro group, as shown in reaction scheme 1, or by trimerization of a molecule containing a bromo group, for example, the trimerization of 6-bromo-1-indanone, with the formation of a truxene intermediate containing a reactive bromo group at the 1st C atom (with nega Gomez-Lor et al., Eur. J. Org. Chem. 2001, 2107-2114). To activate the intermediate at the 2nd C-atom, said intermediate can be reacted with molecular bromine, resulting in an activated intermediate containing reactive bromo groups at the 2nd C-atom, as described by Gomez-Lor et al. in Eur. J. Org. Chem. 2001, 2107-2114. Alternatively, the intermediate can be nitrated and the nitro groups reduced to form an intermediate with reactive amino groups at the 2nd C atom.

If the compounds of formula (IX) and (X) contain a linker group L, then the specified linker group is replaced by a reactive group, providing for joining to the intermediate compound. L or the precursor L is reacted with the specified intermediate compound using methods known in the art. In the next step, X or X ′ is added to form compounds of formula (IX) or (X).

In another embodiment, a building block is made up of LX or L-X ', which is then reacted with the intermediate described above to form compounds of formula (IX) or (X). If X and / or X 'contain COOH groups, then protection of these groups may be required. Suitable protecting groups are known in the art. X can be converted to X 'by a possible deprotection and complexation reaction with a suitable paramagnetic metal ion M, preferably in the form of a salt thereof (for example, acetate Gd (III) or Gd (III) Cl ₃ ).

The compounds of formula (XI) and (XII) can be synthesized according to path 1. The first building block, that is, a core having n R groups attached to it, where said R groups contain reactive amino groups or can be synthesized as described by LMWerbel et al. in J. Org. Chem. 29, 1964, 967-968, or commercially available. Briefly, the first building block can be synthesized as follows:

If the compounds of formula (XI) and (XII) contain a linker group L, then the specified linker group is replaced by a reactive group, providing for the attachment to the first building block. L or the precursor L is reacted with said first building block using methods known in the art. In the next step, X or X ′ is added to form compounds of formula (XI) or (XII).

In another embodiment, a building block is made up of LX or L-X ', which is then reacted with the first building block described above to form compounds of formula (XI) or (XII). If X and / or X 'contain COOH groups, then protection of these groups may be required. Suitable protecting groups are known in the art. X can be converted to X 'by a possible deprotection and complexation reaction with a suitable paramagnetic metal ion M, preferably in the form of a salt thereof (for example, acetate Gd (III) or Gd (III) Cl ₃ ).

The compounds of formula (XIII) and (XIV) can be synthesized according to path 1. The first building block, that is, a hydroxyl-substituted cyclohexyl core having 3 reactive groups attached to it, for example amino groups, can be synthesized as follows:

R or a reactive precursor R is reacted with the above first building block to form a second building block consisting of a hydroxyl-substituted cyclohexyl core and R. If the compounds of formula (XIII) and (XIV) contain a linker group L, then the specified linker group replaced by a reactive group, providing accession to the second building block. L or the precursor L is reacted with said second building block using methods known in the art. In the next step, X or X ′ is added to form compounds of formula (XIII) or (XIV).

In another embodiment, a building block is made up of LX or L-X ', which is then reacted with the second building block described above to form compounds of formula (XIII) or (XIV). If X and / or X 'contain COOH groups, then protection of these groups may be required. Suitable protecting groups are known in the art. X can be converted to X 'by a possible deprotection and complexation reaction with a suitable paramagnetic metal ion M, preferably in the form of a salt thereof (for example, acetate Gd (III) or Gd (III) Cl ₃ ).

The invention is illustrated by examples in the corresponding section of this patent application.

The compounds of formula (II) and their preferred embodiments can be used as MR contrast agents. For this purpose, the compounds of formula (II) are prepared with conventional physiologically acceptable carriers, such as aqueous carriers, for example water and buffer solution, and possibly excipients.

Therefore, according to a further aspect of the present invention, there is provided a composition comprising a compound of formula (II) or its preferred embodiments and at least one physiologically acceptable carrier.

According to an additional aspect of the present invention, there is provided a composition comprising a compound of formula (II) and its preferred embodiments and at least one physiologically acceptable carrier for use as an agent in MR imaging or as an agent in MR spectroscopy.

In order to use these compositions as agents for MR imaging or spectroscopy of a human or non-human animal, it is necessary that they be suitable for administration to the specified organism. The compounds of formula (II) or their preferred embodiments and, optionally, pharmaceutically acceptable excipients and additives may be suitably suspended or dissolved in at least one physiologically acceptable carrier, for example, water or buffer solutions. Suitable additives include, for example, physiologically compatible buffers like tromethamine hydrochloride, chelators such as DTPA, DTPA-BMA or compounds of formula (I) or their preferred embodiments, weak complexes of physiologically acceptable ions such as calcium chelates, for example calcium DTPA, CaNaDTPA -BMA, compounds of formula (I) or their preferred embodiments, where X complexes with Ca ²⁺ or CaNa salts of formula (I) or their preferred embodiments, calcium or sodium salts like calcium chloride, calcium ascorbate, gluconate calcium or calcium lactate. In addition, excipients and additives are described in, for example, WO-A-90/03804, EP-A-463644, EP-A-258616 and US 5876695, the contents of which are incorporated herein by reference.

Another aspect of the invention is the use of a composition comprising a compound of formula (II) or its preferred embodiments and at least one physiologically acceptable carrier, as an agent in MR imaging or as an agent in MR spectroscopy.

Another aspect of the present invention is a method of MR imaging and / or MR spectroscopy, in which a composition comprising a compound of formula (II) or its preferred embodiments and at least one physiologically acceptable carrier is administered to a subject and the subject undergoes an MR procedure, in which MR signals emanating from the subject or parts of the subject in which the composition is distributed are detected, and according to the detected signals, MR tomograms and / or MR spectra are possibly generated.

In a preferred embodiment, the subject is a living organism of a human or non-human animal.

In a further preferred embodiment, the composition is administered in an amount that is effective in improving contrast, that is, in an amount suitable for improving contrast in an MR procedure.

In a preferred embodiment, the subject is a living person or a non-human living animal, and the method of MR imaging and / or MR spectroscopy is a method of MR angiography, more preferably a method of MR peripheral angiography, renal angiography, superior aortic angiography, intracranial angiography or pulmonary angiography.

In another preferred embodiment, the subject is a living person or a non-human living animal, and the method of MR imaging and / or MR spectroscopy is a method for MR detection of a tumor or a method for visualizing tumor contours.

According to another aspect of the invention, there is provided a method of MR imaging and / or MR spectroscopy, in which a subject who has previously been administered a composition comprising a compound of formula (II) or its preferred embodiments and at least one physiologically acceptable carrier is subjected to an MR procedure, in which MR signals emanating from the subject or parts of the subject in which the composition is distributed are detected, and according to the detected signals, MR tomograms and / or MR spectra are possibly generated.

The term “previously introduced” means that the method as described above does not comprise the step of administering said composition to said subject. The introduction of the composition is carried out before the method as described above, that is, before the start of the method of MR imaging and / or MR spectroscopy according to the invention.

Examples

Example 1: Preparation of 1,3,5-tris- (N- (DO3A-acetamido) -N-methyl-4-amino-2-methyl-phenyl) - [1,3,5] triazinan-2,4,6 trion (22), a compound of formula (I), and its gadolinium derivative (23), a compound of formula (II)

1a) Preparation of 2-methyl-4-nitrophenylisocyanate (14)

2-Methyl-4-nitroaniline (35.0 g, 230 mmol) was dissolved in ethyl acetate (400 ml) and cooled to 0 ° C. Phosgene (180 ml, 20% in toluene) was added dropwise over 30 minutes, and white salt immediately precipitated. After the final addition, the mixture was left so that the temperature slowly rose to room temperature, and then the reaction mixture was brought to a reflux state (about 100 ° C). The reaction mixture was refluxed for 2 hours and 30 minutes, after which 200 ml of solvent was distilled off, then the temperature was lowered to 80 ° C and phosgene (140 ml, 20% in toluene) was added dropwise. After the final addition, the reaction solution was refluxed for 3 hours, allowed to cool to room temperature and concentrated to dryness. The brown / yellow material was dissolved in diethyl ether (250 ml), filtered and concentrated to give a pale brown powder (36 g, 88%).

1b) Preparation of 1,3,5-tris- (4-nitro-2-methyl-phenyl) - [1,3,5] triazinan-2,4,6-trion (15)

DMSO (dimethyl sulfoxide, 50 ml) was added to 2-methyl-4-nitrophenyl isocyanate (36.0 g) in a 250 ml flask, and the flask was sealed with a glass stopper, which was fixed with a plastic clip. The flask was immediately immersed in an oil bath heated to 85 ° C, and the dark brown reaction solution was heated for 16 hours 30 minutes. The oil bath was removed and the reaction solution was allowed to cool to room temperature, after which it was poured into water (800 ml), sonicated, and the precipitate was filtered off. The filter cake was added to ethanol (500 ml) and refluxed for 4 hours, then allowed to cool to room temperature and the product was filtered off as an off-white powder (28.1 g, 78%).

1c) Preparation of 1,3,5-tris- (4-amino-2-methyl-phenyl) - [1,3,5] triazinan-2,4,6-trion (16)

1,3,5-Tris- (4-nitro-2-methyl-phenyl) - [1,3,5] triazinan-2,4,6-trion (2.86 g, 5.4 mmol) was dissolved in THF (70 ml). HCl (4.5 ml, 6M), H ₂ O (18 ml) and Pd / C (0.6 g, 10%) were added. The reaction vessel was evacuated and filled with argon (three cycles), then hydrogenated with a Parr hydrogenation apparatus (60 psi, 414 kPa). After 2 hours, excess hydrogen was removed using a membrane pump and Pd / C (10%) was filtered. The clear reaction solution was concentrated to the absence of THF, and the pH was adjusted to 7 with NaHCO ₃ (approximately 3.7 g). The aqueous phase was extracted with ethyl acetate (3 × 100 ml), and the combined organic phases were dried with MgSO ₄ , filtered and concentrated to give a brown powder. The crude product was recrystallized from methanol to give an off-white powder (1.9 g, 80%).

1d) Preparation of 1,3,5-tris- (4-formamido-2-methyl-phenyl) - [1,3,5] triazinan-2,4,6-trion (17)

Formic acid (175 ml) was placed in a 500 ml round-bottom flask, ice-cooled. Acetic anhydride (15 ml, 0.16 mol) was added, and the yellow solution was stirred under argon for 1 h at 0 ° C. Triamine 16 (8.7 g, 0.020 mol) was added to this solution and the ice bath was removed. After stirring under argon at room temperature for 30 minutes, HPLC analysis (high performance liquid chromatography) showed that the reaction was complete. The solvent was removed in vacuo, and the brown sticky residue was suspended in H ₂ O and filtered. Then it was thoroughly washed with H ₂ O to ensure removal of all acid. The product was a pale brown solid (10.2 g, 99%).

1e) Preparation of 1,3,5-tris- (N-formyl-N-methyl-4-amino-2-methyl-phenyl) - [1,3,5] triazinan-2,4,6-trion (18 )

All glassware was thoroughly dried in an oven; DMF (dimethylformamide) was dried over 4 Å molecular sieves.

Li (Me ₃ Si) ₂ N (116 ml, 0.116 mol, 1M in hexane) was added to a DMF solution (115 ml) 17 (10.2 g, 0.0193 mol) in a 500 ml round-bottom flask. The reaction mixture, which changed from a light brown solution to a red-brown suspension, was stirred under argon for 1 hour. Methyl iodide (12.2 ml, 0.196 mol) was added, and the reaction mixture was stirred for 2 hours or until complete methylation, which could be determined by HPLC. Hexane was removed on a rotary evaporator, and the residue was poured into a solution of NaH ₂ PO ₄ (1300 ml, 100 mmol) with vigorous stirring. The resulting precipitate 18 was filtered off as a pale solid (6.7 g, 60%).

1e) Preparation of 1,3,5-tris- (N-methyl-4-amino-2-methylphenyl) - [1.3.5] triazinan-2,4,6-trion (19)

Dioxane (52 ml), HCl (52 ml, 6M) and 18 (6.5 g, 11 mmol) were mixed in a 250 ml round bottom flask to form a pale suspension. The reaction mixture was heated under argon until reflux for 30 minutes. The resulting yellow solution was allowed to cool to room temperature, and then the solvents were removed on a rotary evaporator. Then, the orange residue was dissolved in 500 ml of H ₂ O and neutralized with saturated NaHCO ₃ solution with vigorous stirring. The precipitate formed was filtered off and washed several times with water to obtain a pale solid (4.7 g, 84%).

1g) Preparation of 1,3,5-tris- (N-chloroacetyl-N-methyl-4-amino-2-methyl-phenyl) - [1,3,5] triazinan-2,4,6-trion (20)

19 (4.6 g, 9.5 mmol) was dissolved in DMA (dimethylacetamide, 15 ml) in a 100 ml round bottom flask, and chloroacetyl chloride (2.6 ml, 33 mmol) was added with stirring at 0 ° C. The reaction mixture was stirred under argon at RT (room temperature) for 30 minutes or until HPLC analysis showed complete chloroacetylation. Then the suspension was poured into a large glass with water (500 ml) with vigorous mechanical stirring. The precipitate formed was filtered off and dried in a vacuum of 0.3 mbar (30 Pa) (6.3 g). The pale solid was dissolved in 70 ml of acetonitrile and poured into 500 ml of H ₂ O with vigorous mechanical stirring. The precipitate formed was filtered off and allowed to dry in a desiccator (6.1 g, 89%).

1h) Preparation of 1,3,5-tris- (N- (tert-butyl ether DO3A-acetamido) -N-methyl-4-amino-2-methyl-phenyl) - [1,3,5] triazinan-2, 4,6-trion (21)

20 (0.50 g, 0.70 mmol) were suspended together with tert-butyl ether DO3A (2.5 g, 4.2 mmol), diisopropylethylamine (910 μl, 5.2 mmol) and acetonitrile (15 ml) in a round bottom 50 ml flask. After sonication, the reaction mixture was stirred at 75 ° C under argon until analysis by LC / MS (liquid chromatography / mass spectrometry) showed a complete combination. Then, solvents were removed on a rotary evaporator, and a crude product (2.9 g) was used in the next reaction step.

1i) Preparation of 1,3,5-tris- (N- (DO3A-acetamido) -N-methyl-4-amino-2-methyl-phenyl) - [1,3,5] triazinan-2,4,6- trion (22)

The crude product 21 (1.9 g) was dissolved in TFA (trifluoroacetic acid, 130 ml) and CH ₂ Cl ₂ (130 ml) and stirred at 50 ° C. under argon. The solution was stirred for 1 h or until analysis by LC / MS showed complete deprotection. Then, solvents were removed on a rotary evaporator, and the residue was dried in vacuo overnight. The crude reaction product (2.4 g) was used in the next reaction step.

1k) Preparation of the gadolinium derivative of 1,3,5-tris- (N- (DO3A-acetamido) -N-methyl-4-amino-2-methyl-phenyl) - [1,3,5] triazinan-2,4, 6-trion (23)

The crude product 22 (2.4 g) was dissolved in water and Gd (OAc) ₃ (1.4 g, 4.2 mmol) was added with stirring. Then they were evacuated (0.3 mbar, 30 Pa), and the reaction was constantly monitored by LC / MS. After complete complexation was detected, the solvents were removed in vacuo. The crude product (3.1 g) was then purified by preparative HPLC (410 mg, 42% of 20).

Compound 23 was dissolved in human blood plasma and the longitudinal relaxability r1 was measured at 37 ° C in the following fields:

0.25 T, measured r1 10.7 mM ¹ s ¹ ;

1.5 T, the measured value of r1 11.6 mm ¹ s ¹ ;

2.35 T, measured r1 10.1 mM ¹ s ¹ ;

3 T, the measured value of r1 9.9 mm ¹ s ¹ .

Compared to other compounds, MP contrast agents known in the art, r1 at 3 T of the compound of the invention described above is much higher. The r1 values for other MRI contrast agents at 3 T in human plasma at 37 ° C (data published in Invest Radiol 2006, Vol.41, 213-221):

Multihance ™: r1 is 6.3 mM ¹ s ¹ ,

Magnevist ™: r1 is 3.3 mM ¹ s ¹ .

Example 2: Preparation of 1,3,5-tris- (N- (DO3A-acetamido) -N-methyl-4-amino-2-methyl-phenyl) benzene (6), a compound of formula (I), and its gadolinium derivative (7), compounds of formula (II)

2a) Preparation of 1,3,5-tris- (4-acetamido-2-methyl-phenyl) benzene (1)

4-Acetamido-2-methylacetophenone (Aldrich, 5.0 g, 26.1 mmol) was melted at 180 ° C. in an open round bottom flask. Trifluoromethanesulfonic acid (Fluka, 250 μl, 2.9 mmol) was added to the mixed homogeneous solution. After 1 h, another 250 μl trifluoromethanesulfonic acid was added. After 5 hours, the thick brown mixture was allowed to cool. The product was purified by preparative HPLC and after lyophilization received 570 mg, 4% yield. The structure was confirmed by NMR analysis.

2b) Preparation of 1,3,5-tris- (4-acetamido-N-methyl-4-amino-2-methyl-phenyl) benzene (2)

To a solution of 1 (654 mg, 1.259 mmol) in dry DMF (20 ml) was added lithium bis (trimethylsilyl) amide (Aldrich, 7.56 ml, 7.56 mmol). The reaction mixture, which varied from a clear brown solution to a thick brown suspension, was stirred under argon for 1 h. Methyl iodide (Fluka, 0.956 ml, 15.36 mmol) was added, the solution became light, and the round bottom flask was wrapped in aluminum foil to prevent exposure to light . The reaction was completed after 2 hours. The solvent was evaporated (rotary evaporator). The mixture of products was dissolved in ethyl acetate and washed with water. The organic phase was dried (Na ₂ SO ₄ ) and evaporated to give 700 mg, 99% yield. The structure was confirmed by LC / MS.

2c) Preparation of 1,3,5-tris- (N-methyl-4-amino-2-methyl-phenyl) benzene (3)

A mixture of 2 (700 mg, 1.246 mmol) and 6M H ₂ SO ₄ (80 ml) was heated using microwave radiation at 120 ° C for 30 minutes. The acid was neutralized with saturated NaHCO ₃ with vigorous stirring. The precipitate formed was filtered off and washed several times with water to obtain a pale solid. The product was purified by preparative HPLC and 130 mg was obtained, 24% yield.

2d) Preparation of 1,3,5-tris- (N-chloroacetyl-N-methyl-4-amino-2-methyl-phenyl) benzene (4)

To a cooled solution (0 ° C) 3 (110 mg, 0.253 mmol) in dry DMF (5 ml) was added 2-chloroacetyl chloride (Fluka, 0.07 ml, 0.884 mmol). Then the reaction mixture was stirred under argon at room temperature for 30 minutes. The solvent was evaporated (rotary evaporator), the product mixture was dissolved in dichloromethane, washed with water and dried (Na ₂ SO ₄ ). Received 109 mg of the product, yield 65%. The structure was confirmed by LC / MS.

2e) Preparation of 1,3,5-tris- (N- (tert-butyl ether DO3A-acetamido) -N-methyl-4-amino-2-methyl-phenyl) benzene (5)

To a suspension of 4 (99 mg, 0.149 mmol) in dry acetonitrile (5 ml) was added tert-butyl ether DO3A (532 mg, 0.894 mmol) and diisopropylethylamine (Fluka, 0.189 ml, 1.103 mmol). After sonication, the reaction mixture was stirred under argon at 75 ° C for 7 hours. The solvent was evaporated (rotary evaporator), and the crude product was used in the next reaction step. The structure was confirmed by LC / MS analysis.

2e) Preparation of 1,3,5-tris- (N- (DO3A-acetamido) -N-methyl-4-amino-2-methyl-phenyl) benzene (6)

The crude product 5 was dissolved in formic acid (20 ml) and refluxed. Deprotection was completed after 3.5 hours. The solution was evaporated (rotary evaporator). The crude product was used in the next step without further purification.

2g) Preparation of the gadolinium derivative of 1,3,5-tris- (N- (DO3A-acetamido) -N-methyl-4-amino-2-methyl-phenyl) benzene (7)

Gadolinium (III) acetate hydrate (Aldrich, 329 mg, 0.984 mmol) was added to the crude product 6 dissolved in water (15 ml). The mixture was stirred at 40 ° C for 1 h. Then, the product mixture was purified by preparative HPLC to obtain 190 mg after lyophilization, yield 62% after 3 stages. The structure was confirmed by LC / MS analysis.

Compound 7 was dissolved in human blood plasma, and longitudinal relaxability r1 was measured at 37 ° C in the following fields:

0.47 T, the measured value of r1 10.6 mm ¹ s ¹ ; and

1.41 T, the measured value of r1 9.4 mm ¹ s ¹ .

Based on the measurements above, for a 3 T field, r1 9 mM ¹ s ^{1 is} calculated in accordance with methods known in the art.

Compared to other compounds, MP contrast agents known in the art, r1 at 3 T of the compound of the invention described above is much higher. The r1 values for other MRI contrast agents at 3 T in human plasma at 37 ° C (data published in Invest Radiol 2006, Vol.41, 213-221):

Multihance ™: r1 is 6.3 mM ¹ s ¹ ,

Magnevist ™: r1 is 3.3 mM ¹ s ¹ .

Example 3: Preparation of the gadolinium derivative of benzene-1,3,5-tris - [((DO3A-acetamido) -3- (N'-methyl-amidophenyl)) - carboxamide] (13), the compounds of formula (II)

3a) Preparation of benzene-1,3,5-tris - [(3-nitro-amidophenyl) -carboxamide] (10)

A solution of 8 (3.0 g, 11 mmol) in acetonitrile (40 ml) was added dropwise to a solution of 9 (5.2 g, 38 mmol) and Et ₃ N (5.2 ml, 38 mmol) in acetonitrile (90 ml ) with vigorous stirring and in an argon atmosphere. After stirring at rt for 3 hours, the solvents were removed on a rotary evaporator. The crude residue was suspended in water, filtered and washed several times with water. The yellow precipitate was washed several times with diethyl ether to remove all residual 2, giving 10 as a pale solid (5.6 g, 87%). The structure was confirmed by LC / MS.

3b) Preparation of benzene-1,3,5-tris- [N-methyl- (3-nitro-amidophenyl) -carboxamide] (11)

All glassware was dried in an oven and anhydrous THF was used. The reaction was carried out under argon. To a suspension of 10 (5.6 g, 9.8 mmol) in THF (175 ml), Li (Me ₃ Si) ₂ (59 ml, 59 mmol) was added with stirring. Upon formation of the anion, the suspension turns into a solution. After 30 minutes, methyl iodide (7.3 ml, 120 mmol) was added. After stirring at rt for 18 hours, the solvents were removed on a rotary evaporator. The residue was suspended in water (250 ml) and neutralized with 1M HCl. The precipitate formed was filtered off and washed three times with water. Pale precipitate 11 was dried overnight in a fume hood (5.7 g, 95%). The structure was confirmed by LC / MS.

3c) Preparation of benzene-1,3,5-tris- [N-methyl- (3-aniline-amidophenyl) carboxamide] (12)

Methanol (200 ml), Pd / C (1.0 g, 10%), HCl (4.2 ml, 32%) and 11 (2.0 g, 3.3 mmol) were mixed in a 500 ml reaction flask. The mixture was hydrogenated at 60 psi (414 kPa) in a Parr apparatus. After complete consumption of H _2, H ₂ O (40 ml) was added and the catalyst was filtered off. Then, methanol was removed on a rotary evaporator, and the resulting aqueous solution was diluted to 100 ml and neutralized with solid NaHCO ₃ . The resulting precipitate was filtered off, yielding 12 as a light brown solid (1.4 g, 82%). The structure was confirmed by LC / MS.

3d) Preparation of the gadolinium derivative of benzene-1,3,5-tris - [((DO3A-acetamido) -3- (N'-methylamido-phenyl)) - carboxamide)] (13)

Compound 12 was converted to the gadolinium derivative of benzene-1,3,5-tris - [((DO3A-acetamido) -3- (N'-methylamidophenyl)) -carboxamide)] (13) using the same reaction conditions as described in synthesis of the gadolinium derivative of 1,3,5-tris- (N- (DO3A-acetamido-N-methyl-4-amino-2-methyl-phenyl) benzene (7), Example 2. The structure was confirmed by LC / MS.

Compound 13 was dissolved in human blood plasma and the longitudinal relaxation of r1 was measured at 37 ° C in the following fields:

1.5 T, the measured value of r1 9.2 mm ¹ s ¹ ;

2.35 T, measured value r1 9.5 mm ¹ s ¹ .

Based on the measurements above, for a 3 T field, r1 of 9.0 mM ¹ s ^{1 is} calculated in accordance with methods known in the art.

Compared to other compounds, MP contrast agents known in the art, r1 at 3 T of the compound of the invention described above is much higher. The r1 values for other MRI contrast agents at 3 T in human plasma at 37 ° C (data published in Invest Radiol 2006, Vol.41,213-221):

Multihance ™: r1 is 6.3 mM ¹ s ¹ ,

Magnevist ™: r1 is 3.3 mM ¹ s ¹ .

Example 4: Preparation of 2,4,6-trimethylbenzene-1,3,5-tris - [(DO3A- (3-acetamido-phenyl)) -N-methylcarboxamide] (35), a compound of formula (I), and its gadolinium derivative (36), the compounds of formula (II)

4a) Preparation of 1,3,5-tris- (bromomethyl) -2,4,6-trimethylbenzene (25)

Glacial acetic acid (185 ml) and hydrobromic acid (33% in acetic acid, 260 ml) were added to mesitylene 24 (44.5 g, 0.37 mol) and p-formaldehyde (36.6 g, 1.22 mol). . The suspension was stirred in argon atmosphere and heated at 95 ° C. After 24 hours, the reaction mixture was destroyed in water (150 ml) and stirred vigorously. The precipitate formed was filtered off and washed thoroughly with water to give compound 25 as a white powder (131.2 g, 89%).

4b) Preparation of 1,3,5-tris- (acetoxymethyl) -2,4,6-trimethylbenzene (26)

NaOAc (17.6 g, 0.21 mol) was added to compound 25 (15.0 g, 37.6 mmol), followed by glacial acetic acid (350 ml). The reaction vessel was sealed with a rubber membrane, which was fixed with a copper wire. The stirred reaction mixture was heated at 140 ° C. for 18 hours, after which the reaction mixture was concentrated to obtain an orange-brown solid. The solid residue was suspended in water (250 ml) and extracted with dichloromethane (250 ml). Then the organic phase was extracted with saturated aqueous NaHCO ₃ (150 ml), and then with water (150 ml). Then the organic phase was dried using Na ₂ SO ₄ and filtered. Solvents were removed to give an orange powder, which was crystallized from isopropanol. The resulting crystals were filtered and washed with cold methanol to give triacetate 26 as a white powder (8.3 g, 65%).

4c) Preparation of 1,3,5-tris- (hydroxymethyl) -2,4,6-trimethylbenzene (27)

To a suspension of compound 26 (15.4 g, 46 mmol) in ethanol (310 ml) was added LiOH monohydrate (7.7 g, 184 mmol). The reaction mixture was refluxed for 18 hours, after which the solvents were removed. The residue was suspended in water (100 ml), filtered and rinsed with water (200 ml), obtaining 27 as a white powder (9.0 g, 94%).

4g) Preparation of 2,4,6-trimethylbenzene-1,3,5-tricarboxylic acid (28)

The oxidizing agent was prepared separately: by portioning the addition of chromium oxide (VI) (21.4 g, 214 mmol) to a mixed solution of sulfuric acid (21.4 ml, 18M). The resulting brown suspension was cooled in an ice bath and water (64 ml) was slowly added to give a red solution. The chromium reagent was added dropwise to a solution of compound 27 (5.0 g, 23.8 mmol) in acetone (278 ml) cooled in an ice bath. The reaction mixture was stirred at 0 ° C for 20 minutes, then left to reach room temperature for 30 minutes, and then placed in an oil bath at 30 ° C for 10 minutes. Then the reaction mixture was destroyed in water (550 ml), extracted three times with ether (200 ml), and the combined organic extracts were washed with water (200 ml). The organic phase was dried with Na ₂ SO ₄ , filtered and evaporated to give crude 28 (4.2 g). White crystals of crude 28 were suspended in water (70 ml), and the pH was adjusted to 7 by addition of NaOH (50 ml, 1M). The resulting light solution was passed through an ion exchange column (Dowex 50 × 8, dimensions: D (diameter): 3 cm, L (length): 7 cm) and was eluted with water (150 ml). The eluent was lyophilized to give a white powder, which was crystallized in boiling acetic acid (100 ml). After cooling, the crystals were filtered and rinsed with acetic acid to give compound 28 as a white powder (3.2 g, 53%).

4e) Preparation of 2,4,6-trimethylbenzene-1,3,5-tri-carboxylic acid chloride (29)

A suspension of 28 (1.0 g, 4.0 mmol) and PCl ₅ (8.2 g, 39.4 mmol) in toluene (10 ml) was refluxed. After 1 h, toluene and excess PCl _{5 were} distilled off at atmospheric pressure. Then created a low vacuum (membrane pump) and drove POCl ₃ , and the temperature of the oil bath never exceeded 155 ° C. The melt that solidified upon cooling (mp (melting point): 125 ° C) was allowed to reach room temperature. The crude reaction mixture was then dissolved in Et ₂ O (40 ml), filtered, and then concentrated to give 29 as a white powder (1.1 g, 94%).

4e) Preparation of 2,4,6-trimethylbenzene-1,3,5-tris - [((N- (3-nitrophenyl)) - carboxamide)] (31)

Compound 29 (0.65 g, 2.1 mmol) and nitroaniline 30 (1.0 g, 7.2 mmol) were dissolved and then refluxed in CH ₃ CN (15 ml) under argon. After 3 hours, the reaction mixture was allowed to cool, and then was added dropwise to a vigorously stirred aqueous HCl solution (500 ml, 1.6M). The precipitate formed was filtered off and rinsed with water (200 ml). The precipitate (1.3 g) was sonicated in a mixture of CHCl ₃ / CH ₃ CN (50/1 ml) to obtain a fine suspension, which was filtered to give compound 31 (0.84 g, 65%).

4g) Preparation of 2,4,6-trimethylbenzene-1,3,5-tris - [(N-methyl-N- (3-nitrophenyl)) - carboxamide] (32)

Compound 31 (0.83 g, 1.35 mmol) was dissolved in THF (40 ml) under argon. Lithium hexamethyldisilazide (8.2 ml, 1M) was added dropwise and after 5 min MeI (1 ml, 16.1 mmol) was added. After 24 hours, the reaction mixture was concentrated and then suspended in H ₂ O (60 ml) by sonication. The suspension was acidified by adding HCl (2 ml, 4M), after which larger particles formed in a finely dispersed suspension, which were filtered to give compound 32 as a fine olive green powder (0.79 g, 88%).

4h) Preparation of 2,4,6-trimethylbenzene-1,3,5-tris- [N-methyl- (3-chloroacetamido-phenyl) -carboxamide] (33)

To compound 32 (1.0 g, 1.52 mmol) was added heptahydrate FeSO ₄ (3.8 g, 13.7 mmol), NH ₄ Cl (2.0 g, 25.5 mmol) and a mixture of ethanol / water ( 60 ml, ratio 4/1). The resulting suspension was stirred at 80 ° C. and zinc powder (0.9 g, 13.7 mmol) was added. After 2 hours, the reaction mixture was allowed to cool and the suspension was filtered. The filtrate was concentrated and sonicated in acetonitrile (100 ml) to give a suspension that was filtered. Chloroacetyl chloride (0.73 ml, 9.1 mmol) was added to the filtrate, after which a suspension formed. After 30 minutes, the reaction mixture was filtered, and the precipitate containing a mixture of mono-, bis- and tris-acetylated aniline was dissolved in DMA (dimethylacetamide, 25 ml). Chloroacetyl chloride (1 ml, 12.5 mmol) and triethylamine (1 ml, 7.2 mmol) were added to the solution. After 30 minutes, two solutions (acetonitrile and DMA) were combined and poured into water (750 ml). The precipitate formed was filtered off and washed with additional water to give compound 33 (0.82 g, 68%).

4i) Preparation of 2,4,6-trimethylbenzene-1,3,5-tris - [((tert-butyl ether DO3A) - (3-acetoamidophenyl)) - N-methylcarboxamide] (34)

Compound 33 (0.81 g, 1.0 mmol) and DO3A (t-Bu) ₃ (2.1 g, 4.1 mmol) were dissolved in CH ₃ CN (30 ml) and N, N- was added under argon atmosphere. diisopropylethylamine (1.2 ml, 7.3 mmol). The reaction mixture was refluxed for 19 hours, after which the solvents were removed to give 34 as a brown syrup, which was used without purification in the next step.

4k) Preparation of 2,4,6-trimethylbenzene-1,3,5-tris - [(DO3A- (3-acetamidophenyl)) - N-methylcarboxamide] (35)

Compound 34 (the crude reaction mixture obtained from 0.81 g of 33) was dissolved in formic acid (25 ml) and refluxed for 1 h, after which the solvent was removed to give compound 35 as a brown syrup, which in the next step used without purification.

4 l) Preparation of the gadolinium derivative of 2,4,6-trimethylbenzene-1,3,5-tris - [(DO3A- (3-acetamidophenyl)) - N-methyl-carboxamide] (36)

The crude reaction mixture containing 35 (obtained from 0.81 g of 33) was dissolved in H ₂ O (25 ml), and Gd (OAc) ₃ (2.0 g, 6.0 mmol) was added to the stirred reaction mixture at room temperature. ) KOAc was added to adjust pH to 5; a vacuum was periodically connected to remove the resulting acetic acid, and additional H ₂ O was added to maintain the reaction volume. After 24 h, the reaction mixture was concentrated and after preparative HPLC, compound 36 was obtained as an off-white powder (0.9 g, 41% after three stages).

Compound 36 was dissolved in human blood plasma and the longitudinal relaxability r1 was measured at 37 ° C in the following fields:

0.235 T, measured r1 9.3 mM ¹ s ¹ ;

0.47 T, the measured value of r1 8.8 mm ¹ s ¹ ;

1.41 T, measured r1 value 7.3 mM ¹ s ¹ .

Based on the measurements given above, for a 3 T field, in accordance with methods known in the art, r1 8.5 mM ¹ s ^{1 was} calculated.

Compared to other compounds, MP contrast agents known in the art, r1 at 3 T of the compound of the invention described above is much higher. The r1 values for other MRI contrast agents at 3 T in human plasma at 37 ° C (data published in Invest Radiol 2006, Vol.41, 213-221):

Multihance ™: r1 is 6.3 mM ¹ s ¹ ,

Magnevist ™: r1 is 3.3 mM ¹ s ¹ .

Example 5: Preparation of 2,4,6-trimethylbenzene-1,3,5-tris - [(2-DO3A-propyl) -3-amidophenyl] carboxamide (39), a compound of formula (I), and its gadolinium derivative ( 40), compounds of formula (II)

5a) Preparation of 2,4,6-trimethylbenzene-1,3,5-tris- [N-methyl - ((2-chloropropyl) -3-amidophenyl) carboxamide)] (37)

To compound 32 (0.28 g, 0.43 mmol) was added heptahydrate FeSO ₄ (1.1 g, 4.0 mmol), NH ₄ Cl (0.5 g, 9.3 mmol) and a mixture of ethanol / water ( 20 ml, ratio 4/1). The resulting suspension was stirred at 80 ° C. and zinc powder (0.25 g, 3.8 mmol) was added. After 1.5 hours, the reaction mixture was allowed to cool and the suspension was filtered. The filtrate was concentrated and sonicated in acetonitrile (20 ml) to give a suspension, which was filtered and diluted with additional acetonitrile (20 ml). 2-Propionyl chloride (0.42 ml, 4.3 mmol) was added, after which a suspension formed. Triethylamine (0.5 ml, 3.6 mmol) was added. After 30 minutes, the reaction mixture was concentrated and poured into water (75 ml). The resulting precipitate was sonicated, filtered and washed with additional water to give compound 37 (0.25 g, 70%).

5b) Preparation of 2,4,6-trimethylbenzene-1,3,5-tris- [N-methyl - ((2- (tert-butyl ether DO3A) propyl) -3-amidophenyl) carboxamide)] (38)

Compound 37 (0.21 g, 0.25 mmol) and DO3A (t-Bu) ₃ (0.52 g, 1.0 mmol) were dissolved in CH ₃ CN (8 ml) and N, N- was added under argon atmosphere. diisopropylethylamine (0.3 ml, 1.8 mmol). The reaction mixture was refluxed for 72 hours, after which the solvents were removed to give 38 as a brown syrup, which was used without purification in the next step.

5c) Preparation of 2,4,6-trimethylbenzene-1,3,5-tris- [N-methyl - ((2-DO3A-propyl) -3-amidophenyl) carboxamide)] (39)

Compound 38 (the crude reaction mixture obtained from 0.21 g 37) was dissolved in formic acid (8 ml) and refluxed for 1 h, after which the solvent was removed to give compound 39 as a brown syrup, which in the next step used without purification.

5 g) Preparation of the gadolinium derivative of 2,4,6-trimethylbenzene-1,3,5-tris- [N-methyl - ((2-DO3A-propyl) -3-amidophenyl) carboxamide)] (40)

The crude reaction mixture containing 39 (obtained from 0.21 g 37) was dissolved in H ₂ O (10 ml), and Gd (OAc) ₃ (0.5 g, 1.5 mmol) was added to the stirred reaction mixture at room temperature. ) To bring the pH to 5, COAc was added. After 24 hours, the reaction mixture was concentrated, and after preparative HPLC, compound 40 was obtained as a white powder. This batch was combined with the second batch to give 0.43 g (17% after three stages of 0.96 g 37).

Compound 40 was dissolved in human blood plasma and the longitudinal relaxability r1 was measured at 37 ° C in the following fields:

0.235 T, measured r1 10.1 mM ¹ s ¹ ;

0.47 T, the measured value of r1 8.6 mm ¹ s ¹ ;

1.41 T, measured value r1 9.1 mmol ¹ s ¹ .

Based on the measurements above, for a 3 T field, r1 9 mM ¹ s ^{1 is} calculated in accordance with methods known in the art.

Compared to other compounds, MP contrast agents known in the art, r1 at 3 T of the compound of the invention described above is much higher. The r1 values for other MRI contrast agents at 3 T in human plasma at 37 ° C (data published in Invest Radiol 2006, Vol.41, 213-221):

Multihance ™: r1 is 6.3 mM ¹ s ¹ ,

Magnevist ™: r1 is 3.3 mM ¹ s ¹ .

Example 6: Preparation of 2,4,6-trimethylbenzene-1,3,5-tris- [N-methyl - [(DO3A- (3-acetamidophenyl)) - N-methyl-carboxamide] (42), a compound of formula (I ), and its gadolinium derivative (43), a compound of formula (II)

6a) Preparation of 2,4,6-trimethylbenzene-1,3,5-tris- [N-methyl - ((2- (tert-butyl ether DO3A) propyl) -3- (N'-methyl-amidophenyl)) -carboxamide)] (41)

The crude compound 34 (obtained from 0.50 g 33) was suspended in THF (20 ml) by sonication. MeI (0.5 ml, 7.5 mmol) was added, followed by NaH (60% in mineral oil, 0.15 g, 3.8 mmol). After 30 minutes, the reaction mixture was diluted with THF (100 ml) and additional amounts of MeI (0.5 ml, 7.5 mmol) and NaH (60%, 0.15 g, 7.5 mmol) were added. After 1 h, an additional amount of NaH (60%, 0.15 g, 7.5 mmol) was added. After 2 hours, the reaction mixture was concentrated to give a brown foam, to which was added an aqueous solution of HCOOH (0.1%, 100 ml). Using mechanical

trituration and sonication gave a finely divided suspension, which was diluted with CH ₂ Cl ₂ (100 ml) and extracted. The organic phase was washed with water (100 ml) and then dried with MgSO ₄ , filtered and concentrated to obtain 1.6 g of 41 as a fine brownish powder, which was used in the next step without further purification.

6b) Preparation of 2,4,6-trimethylbenzene-1,3,5-tris- [N-methyl - ((2-DO3A-propyl) -3- (N'-methyl-amidophenyl)) - carboxamide)] (42 )

Compound 41 (the crude reaction mixture obtained from 0.50 g 37) was dissolved in formic acid (20 ml) and refluxed for 90 minutes, after which the solvent was removed to give compound 42 as a brown syrup, which in the next step used without purification.

6c) Preparation of the gadolinium derivative of 2,4,6-trimethylbenzene-1,3,5-tris- [N-methyl - ((2-DO3A-propyl) -3- (N'-methyl-amidophenyl)) - carboxamide)] (43)

The crude reaction mixture containing 42 (obtained from 0.50 g 37) was dissolved in H ₂ O (20 ml) and Ca (OAc) _{3 was} added at room temperature

(1.3 g, 3.9 mmol). To bring the pH to 4, COAc was added. After 2 hours, the reaction mixture was washed with CH ₂ Cl ₂ (30 ml) and the aqueous phase was filtered (PALL, 0.45 μm PTFE ACRODISC CR) to give a clear brownish solution. The solution was concentrated, and after preparative HPLC, compound 43 was obtained as an off-white powder (0.53 g, 38% after four steps).

Compound 43 was dissolved in human blood plasma and the longitudinal relaxability r1 was measured at 37 ° C in the following fields:

0.235 T, the measured value of r1 12 mm ¹ s ¹ ;

0.47 T, the measured value of r1 10.6 mm ¹ s ¹ ;

1.41 T, the measured value of r1 9 mm ¹ s ¹ .

Based on the measurements above, for a 3 T field, r1 of 8.2 mM ¹ s ^{1 was} calculated in accordance with methods known in the art.

Compared to other compounds, MP contrast agents known in the art, r1 at 3 T of the compound of the invention described above is much higher. The r1 values for other MRI contrast agents at 3 T in human plasma at 37 ° C (data published in Invest Radiol 2006, Vol.41,213-221):

Multihance ™: r1 is 6.3 mM ¹ s ¹ ,

Magnevist ™; r1 is 3.3 mM ¹ s ¹ .

Example 7: Preparation of 2,4,6-trimethylbenzene-1,3,5-tris- [N-methyl - ((2-DO3A-propyl) -3- (N'-methylamidophenyl)) carboxamide)] (45), the compounds of formula (I) and its gadolinium derivative (46), the compounds of formula (II)

7a) Preparation of 2,4,6-trimethylbenzene-1,3,5-tris- [N-methyl - ((2- (tert-butyl ether DO3A) propyl) -3- (N'-methyl-amidophenyl)) -carboxamide)] (44)

To compound 38 (crude reaction mixture obtained from 0.45 g 37), THF (70 ml) and DMA (5 ml) were added; sonication resulted in a yellowish precipitate solution. The reaction mixture was stirred under argon and MeI (0.4 ml, 6.4 mmol) was added, followed by NaH (60%, 0.13 g, 3.3 mmol). After 120 minutes, additional amounts of MeI (0.4 ml, 6.4 mmol) and NaH (60%, 0.13 g, 3.3 mmol) were added. After 150 min, an additional amount of NaH (60%, 0.13 g, 3.3 mmol) was added. After 200 min, the reaction mixture was concentrated and dissolved in dichloromethane (200 ml). The organic phase was extracted with HCOOH (0.5%, 200 ml), then with water (200 ml), dried with MgSO ₄ , filtered and concentrated. The crude reaction mixture was used in the next step without further purification.

7b) Preparation of 2,4,6-trimethylbenzene-1,3,5-tris- [N-methyl - ((2-DO3A-propyl) -3- (N'-methyl-amidophenyl)) - carboxamide)] (45 )

To compound 44 (crude reaction mixture obtained from 0.45 g 37) dissolved in dichloromethane (25 ml), TFA (10 ml) was added under argon atmosphere. The reaction mixture was refluxed for 3 hours, after which the solvents were removed to give compound 45 as a brown syrup, which was used without purification in the next step.

7c) Preparation of the gadolinium derivative of 2,4,6-trimethylbenzene-1,3,5-tris [N-methyl - ((2-DO3A-propyl) -3- (N'-methyl-amidophenyl)) - carboxamide)] ( 46)

The crude reaction mixture containing 45 (obtained from 0.45 g 37) was dissolved in H ₂ O (40 ml) and Gd (OAc) ₃ (1.0 g, 3.0 mmol) was added to the stirred reaction mixture at room temperature. . To bring the pH to 5, COAc was added. After 24 hours, the reaction mixture was concentrated, and after preparative HPLC, compound 46 was obtained as a white powder (0.17 g, 14% after four steps).

Compound 46 was dissolved in human blood plasma and the longitudinal relaxability r1 was measured at 37 ° C in the following fields:

0.235 T, measured r1 10.9 mM ¹ s ¹ ;

0.47 T, measured r1 10.1 mM ¹ s ¹ ;

1.41 T, measured r1 value 8.9 mM ¹ s ¹ .

Based on the measurements above, for a 3 T field, r1 9 mM ¹ s ^{1 is} calculated in accordance with methods known in the art.

Compared to other compounds, MP contrast agents known in the art, r1 at 3 T of the compound of the invention described above is much higher. The r1 values for other MRI contrast agents at 3 T in human plasma at 37 ° C (data published in Invest Radiol 2006, Vol.41, 213-221):

Multihance ™: r1 is 6.3 mM ¹ s ¹ ,

Magnevist ™: r1 is 3.3 mM ¹ s ¹ .

Example 8: Preparation of 2,7,12-tris- (DOTA-amido) -5.5 ', 10.10', 15.15'-hexakis-methoxymethyl) -ruxen (51), a compound of formula (I), and its gadolinium derivative (52), the compounds of formula (II)

8a) Preparation of 5.5 ', 10.10', 15.15'-hexakis (methoxymethyl) truxen (48)

Compound 47 (5 g, 14.6 mmol) was dissolved in THF (100 ml) and then cooled to −70 ° C. under a nitrogen atmosphere. Then n-butyllithium (22 ml, 2M in cyclohexane) was added and the reaction mixture was allowed to reach ambient temperature. Then, chloromethyl methyl ether (3.66 ml, 48.2 mmol) was added, and the reaction mixture was stirred at ambient temperature for 2 hours. Then, the reaction mixture was extracted with brine and dichloromethane. The organic phase is dried and concentrated. The residue was dissolved in THF (100 ml) and then cooled to −70 ° C. under a nitrogen atmosphere. Then n-butyllithium (22 ml, 2M in cyclohexane) was added and the reaction mixture was allowed to reach ambient temperature. Then chloromethyl methyl ether (3.66 ml, 48.2 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 hours. After that, the reaction mixture was extracted with brine and dichloromethane. The organic phase was dried and concentrated to give compound 48 (8.8 g, 14.6 mmol).

8b) Preparation of 2,7,12-trinitro-5,5 ', 10,10', 15,15'-hexakis (methoxymethyl) -truxen (49)

Compound 48 (8.8 g, 14.6 mmol) was slowly added to an ice-cooled mixture of fuming HNO ₃ (50 ml) and acetic anhydride (8.3 ml, 88 mmol). Especially make sure that the temperature never exceeds 5 ° C. Then the reaction mixture was poured into ice-water, and the precipitate was filtered off to obtain compound 49.

8c) Preparation of 2,7,12-triamino-5,5 ′, 10,10 ′, 15,15′-hexakis (methoxymethyl) -truxen (50)

Compound 49 (10.8 g, 14.6 mmol) was dissolved in THF (100 ml) and Pd / C (3 g, 10%) was added. The reaction mixture is treated with molecular hydrogen in a high pressure reactor at 10 bar (1000 kPa) with vigorous stirring. After 3 hours, the reaction mixture was filtered and concentrated to give compound 50.

8 g) Preparation of 2,7,12-Tris- (DOTA-amido) -5.5 ', 10.10', 15.15'-hexakis (methoxymethyl) Truxen (51)

4,7,10-Tricarboxymethyl-tert-butyl ester of 1,4,7,10-tetraazacyclododecane-1-acetate (DOTA (tert-Bu) ₃ ) (33.7 g, 48.2 mmol), which is obtained as described by Heppeler, A in Chem. Eur. J. 1999, 5, 1974-1981, HATU (O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) (18.3 ml, 48.2 mmol), and DIPEA ( (N, N'-diisopropylethylamine) (8.2 ml, 48.2 mmol) was preincubated in DMF (500 ml). After 10 minutes, compound 50 (9.5 g, 14.6 mmol) and DIPEA (8.1 ml, 48.2 mmol) in a solution in DMF (100 ml). The reaction mixture was stirred for 3 hours and then diluted with water and extracted with ethyl acetate. The organic phase was dried, concentrated and dissolved in formic acid (100 ml). The resulting solution was boiled. under reflux for 1 h and then concentrated to give compound eniya 51.

8d) Preparation of the gadolinium derivative of 2,7,12-tris (DOTA-amido) -5.5 ', 10.10', 15.15'-hexakis (methoxymethyl) truxen (52)

Compound 51 (26.4 g, 14.6 mmol) was dissolved in water and Gd (OAc) ₃ (16.1 g, 48.2 mmol) was added. After 24 hours, the reaction mixture was concentrated and purified by preparative HPLC to give compound 52.

An example composition for use as an agent in MR imaging or MR spectroscopy No. Ingredients amount one. Active ingredient (compound of formula (II)) 15 mmol 2. Physiologically acceptable carrier (water for injection) 30 ml

The starting components are mixed to obtain an aqueous composition that is loaded into the vial (s).

Claims (8)

1. The compound of formula (II), consisting of a core and groups -RL-X 'attached to the specified core,

where A is an aromatic ring selected from a [1,3,5] triazinan-2,4,6-trion ring or a benzene ring optionally substituted with one or more C ₁ -C ₃ alkyl;
R is a residue of a benzene ring optionally substituted with C ₁ -C ₃ alkyl, and R may be attached to A by a moiety of formula (IIIb)

where R ^b means C ₁ -C ₃ -alkyl;
L is a linker moiety —CZ ¹ Z ² —CO — N (R ^b ) - *;
where * means the addition of R to the specified linker moiety, Z ¹ and Z ² represent hydrogen, or Z ¹ represents hydrogen and Z ² represents methyl, and R ^b represents H or C ₁ -C ₃ alkyl;
X 'means a paramagnetic chelate consisting of a chelator X and a paramagnetic metal ion M,
where X represents the remainder of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), M represents Gd ³⁺ ;
n is 3;
or in the case where A means a benzene ring, R may be a cyclic moiety fused to the core A, which corresponds to the following formula (X):

where Qa is C (Rc) ₂ , and Rc is CH ₂ OCH ₃ ; L and X 'have the meanings indicated above. 2. A composition for use as an agent in MR (magnetic resonance) imaging or as an agent in MR spectroscopy, containing the compound according to claim 1 and at least one physiologically acceptable carrier. 3. The use of the composition according to claim 2 as a contrast agent in MR imaging or as an agent in MR spectroscopy. 4. The compounds of formula (I), consisting of a core and -RLX groups attached to the specified core,

where A is an aromatic ring selected from a [1,3,5] triazinan-2,4,6-trion ring or a benzene ring optionally substituted with one or more C ₁ -C ₃ alkyl;
R is a residue of a benzene ring optionally substituted with C ₁ -C ₃ alkyl, and R may be attached to A by a moiety of formula (IIIb)

where R ^b means C ₁ -C ₃ -alkyl;
L is a linker moiety —CZ ¹ Z ² —CO — N (R ^b ) - *;
where * means the attachment of R to the specified linker group, Z ¹ and
Z ² represents hydrogen, or Z ¹ represents hydrogen and Z ² represents methyl, and R ^b represents H or C ₁ -C ₃ alkyl;
X is a chelator representing a residue of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A);
n is 3;
or in the case where A means a benzene ring, R may be a cyclic moiety fused to the core A, which corresponds to the following formula (IX):

where Qa is C (Rc) ₂ , and Rc is CH ₂ OCH ₃ ; L and X have the meanings indicated above. 5. The method of producing compounds according to claim 4, including
a) the use as the first building block of core A, which is substituted by reactive groups involving the addition of R;
b) the interaction of R or its predecessor with the specified first building block with the formation of the second building block, consisting of a core A and R;
c) the interaction of L or its predecessor with the specified second building block with the formation of the third building block, consisting of a core A, R and L; and
d) the interaction of X or its predecessor with the specified third building block. 6. The method of producing compounds according to claim 4, including
a) the use of the first building block, consisting of a core A and R, condensed with A or attached to A, where R is substituted by reactive groups involving the addition of L;
b) the interaction of L or its predecessor with the specified first building block with the formation of the second building block, consisting of a core A, R and L, and
c) the interaction of X or its predecessor with the specified second building block. 7. A method of producing compounds according to claim 4, including
a) trimerization of a monomer containing a group, which after trimerization forms A, wherein said monomer further comprises R containing a reactive group or its precursor, comprising the addition of L or its precursor to form an intermediate compound;
b) the interaction of L or its predecessor with the specified intermediate compound; and
C) the interaction of X or its predecessor with the reaction product of stage b). 8. The method of producing compounds according to claim 1, comprising the implementation of any of the methods according to claims 5-7 and the implementation of the next step, comprising complexing the reaction product of any of these methods according to claims 5-7 with a paramagnetic metal ion Gd ³⁺ .