ES2354320B2 - MAGNETICALLY MARKED CYCLOPEPTIDES WITH LANTANID COMPLEXES. - Google Patents

Abstract

Magnetically labeled cyclopeptides with lanthanide complexes.

The present invention is directed to the use of cyclopeptides capable of effectively coordinating elements of the lanthanide series, preferably metal ions such as Gd3 +. Said cyclic units can be self-assembled giving rise to the formation of magnetically labeled nanotubular structures. In this way, nanotube preparation can be carried out for application as contract agents for Image by Magnetic Resonance (MRI). Due to the shape of its aggregates supramolecular possess anisotropic magnetic properties with Applications in the early detection of various cancers and problems of atherosclerosis. Second, this patent is also aimed at the synthesis of intermediates useful for obtaining metal cyclopeptides and chelating agents.

Description

Magnetically labeled cyclopeptides with lanthanide complexes.

Technical sector

The present invention is directed to the compounds of formula VI, magnetically labeled cyclopeptide with lanthanide complexes with anisotropic magnetic properties due to the shape of their supramolecular aggregates, which makes them useful as contrast agents for Magnetic Resonance Imaging (MRI) and especially for the early detection of cancers and / or atherosclerosis; it is also directed to the compounds of formula I, intermediates useful in the preparation of the compounds of formula VI; and the procedure for obtaining these compounds
cough.

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Background

Magnetic Resonance Imaging (MRI) It is one of the most powerful tools in diagnosis current clinical Its effectiveness appears linked both to the development of more efficient image sequences, such as the preparation of new contrast agents (ACs) that allow to increase the quality, resolution and specificity of RM images.

The main determinants of contrast in an MR image is the relaxation times of the protons of the water, T1 and T2. So, when the contrast difference between healthy and pathological regions of a tissue is very small due to small variations in relaxation times, the use of ACs is highly beneficial. ACs are substances capable of significantly alter the relaxation times of protons of water in the tissues where they are distributed. The use of these agents is a great improvement in clinical diagnosis, in terms of high specificity, better characterization of tissues, reduction of artifacts in the image and information Functional of them. The most commonly used ACs in the clinic are the paramagnetic gadolinium chelates; their effectiveness to act as an AC is valued, first of all, by the determination of its relaxivity, that is to say by the increase in relaxation of water protons.

In the last 15 years, they have been published numerous articles aimed at the study of structure and dynamics of the complexes of Gd (III), which has meant a great advance in the understanding of structural parameters, dynamic and electronic determinants in the relaxation of these complex. The most commonly used contrast agents in image Diagnostic are gadolinium complexes derived from acid diethylenetriaminepentaacetic acid (DTPA) and acid 1,4,7,10-tetraaza-1,4,7,10-cyclododecanotetraacetic acid (DOTA).

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one

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Currently, research in this field is focused on the design and synthesis of new chelating agents that have a high affinity for the corresponding paramagnetic metal, as well as high relajativity. Recently, a new series of pyrazolylethyldiethylenetriaminetetraacetic acids whose Gd (III) complexes have higher magnetic properties than those used in clinics (P. Ballesteros García, E. Pérez Mayoral, Heterocyclic ligands and their gadolinium complexes ( III) with biomedical applications, PCT Int. Appl., (2006) WO 2006051142; P. Ballesteros García, E. Pérez Mayoral, 1-Pyrazolylethyl-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acids Application of its gadolinium (III) complexes in clinical diagnosis, PCT Int. Appl., (2006), WO 2006051142. Recently the research group of Prof. Paloma Ballesteros and Sebastián Cerdán (UNED-CSIC) has demonstrated, through the use of carbon nanotubes containing 1.8 and 0.7% by weight of cobalt and nickel, respectively, which have anisotropic magnetic properties (S. Cerdán García-Esteller, P. López Larrubia, L. Nieto Charques, P. Crossbow ros García, E. Pérez Mayoral, V. Negri. Tubular nanostructured materials with anisotropic magnetic properties. Obtaining procedure and its applications,
P200800024).

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In general, ACs can be considered as substances capable of giving information about the biological environment of the tissues. The early diagnosis of cancer and diseases vascular, such as atherosclerosis, along with the follow-up of a effective therapy, can be performed using new capable probes of giving information about specific events that occur both at the cellular and molecular level. More specifically, the atherosclerosis is a systemic disease characterized by the accumulation of lipid plaques on the vessel walls blood, being one of the main causes of mortality in Developed countries worldwide. Therefore, the development of new agents to diagnose, early, this sickness.

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Description of the invention

A new invention is described in the present invention. generation of contrast agents (Acs) based on cyclopeptides, capable of self-assembly through links hydrogen giving rise to tubular structures, whose lanthanide complexes have magnetic properties anisotropic The tubular nature of cyclopeptide ligands It is a very important feature which allows us to distinguish between turbulent and laminar flow, thus increasing the efficacy of ACs for use in MRI. One of the main advantages of the invention is its biocompatibility due to the character peptide

It is also easy to modify the structure cyclopeptide amino acid without altering its ability to self-assemble and form nanotubes, as well as their properties paramagnetic, since only one of the amino acids that make up the cyclopeptide is used for binding with the chelating ligand of the lanthanide

In one aspect the invention is directed to the intermediates of general formula I

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2

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his racemic mix, each of his enantiomers, their diastereomers or their pharmaceutically salts acceptable, in where

R1 is selected from H or the radicals linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl, where each of these radicals is optionally substituted by one or more substituents, identical or different, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONR2), amine (-NH2), mono (-NHR) or disubstituted amine (-NRR '), mono (-CONHR) or disubstituted (-CONRR') carboxyamide, urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONRR '), aminocarbonoyl (-NRCOOR'), aryl, bicycles, heterocyclic nitrogen, oxygenated or saturated or unsaturated sulphide saturated containing 5 or 6 members;

R 2 and R 4 are selected independently between H or linear alkyl radicals or branched, linear or branched alkenyl, where each of these radicals is optionally substituted by one or more substituents, identical or different, independently chosen between halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono amine (-NHR) or disubstituted (-NRR '), mono carboxyamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR or -NHCONRR '), or trisubstituted (-NRCONR'R' '), aminocarbonoyl (-NRCOOR '), aryl, bicyclo, nitrogen heterogenated, oxygenated or saturated or unsaturated sulphide containing 5 or 6 members;

R 3 is selected from H or the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more identical or different substituents, independently chosen from halogen , hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN) , nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR' amine) ), monocarbonamide mono (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR' or -NHCONRR '), or trisubstituted (-NRCONR'R''), aminocarbonoyl (-NRCOOR') , mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), any of said cyclic radicals possibly being modified by one or more substituents, identical or different, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate
(-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenated, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members ;

q is an integer selected in a way independent between 0, 1, 2, 3, 4 or 5;

thus the number of amino acids that constitute the cyclopeptide is variable according to the value of q; Likewise depending on the value of q there will be a variable number of substituents R 6, which will be independently selected from

H or the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more identical or different substituents, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy
(-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (- NH 2), mono (-NHR) or disubstituted (-NRR '), monocarbonamide (CONHR) or disubstituted (-CONRR'), mono urea (-NHCONHR), di (-NRCONHR 'or -NHCONRR') amine , or trisubstituted (-NRCONR '
R ''), aminocarbonoyl (-NRCOOR '), mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), any of said cyclic radicals possibly modified by one or more substituents, identical or different, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy ( -OCOR), acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate
(-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenous, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members;

R 5 is one of the polyethylene derivatives cyclic or acyclic of general formula (II) or (III)

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3

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in which Z may be selected from H, Li, Na, K, N- methylglucosamine, benzyl or tert-butyl ( t- Bu);

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X represents a group selected from amides (-CONH- or -NHCO-), amines (-NR-), esters (-COO- or -OCO-),
ethers (-O-), thioethers (-S-), disulfides (-SS-), ureas (-NHCONH-), carbamates (-NHCOO- or -OCONH-), mono- or bicyclic aryls or heteroaryls nitrogen, oxygenated or sulphurated , saturated or unsaturated containing 5 or 6 members, or connectors of general formula IV

4

where Ar represents a group mono or bicyclic aryl, or nitrogenous, oxygenated heteroaryl or sulphides containing 5 or 6 members;

m, n, p are whole numbers selected from independently between 0, 1, 2, 3, 4 or 5;

A, B, D, are selected independently between the atoms of nitrogen (N), sulfur (S), oxygen (O) or carbon (C); in case said atoms are N or C, they are optionally substituted by one or more substituents, identical or different, independently chosen from hydrogen, halogen, hydroxy (-OH), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR ') amine, monocarboxyamide mono (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONR'R' '), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), aryl, bicycles, heterocyclic nitrogen, oxygenated or sulphured, saturated or not saturated containing 5 or 6 members, linear alkyl radicals or branched, linear or branched alkenyl, linear alkynyl or branched, any of these radicals may be optionally substituted by one or more identical substituents or different, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono amine (-NHR) or disubstituted (-NRR '), mono carboxyamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR' or -NHCONRR '), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), heterocyclic nitrogen, oxygenated or saturated or unsaturated sulphide saturated containing 5 or 6 members;

m is an integer selected in a way independent between 0, 1, 2, 3, 4 or 5. There are as many R 7 as the value that adopts m, said R 7 are selected so independent between H or linear or branched alkyl radicals, linear or branched alkenyl, any one of which may be radicals eventually substituted by one or more substituents, identical or different, chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR ') amine, monocarboxyamide mono (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR or -NHCONRR '), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), aryl, bicycles, heterocyclic nitrogen, oxygenated or saturated or unsaturated sulphide saturated that contains 5 or 6 members.

R, R 'and R' 'can be selected so independent between hydrogen or linear alkyl radicals or branched, linear or branched alkenyl, linear alkynyl or branched, cycloalkyl, cycloalkenyl, bicycloalkyl, mono or bicycloaryl, saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S); being able be any of said radicals eventually substituted by one or more substituents, identical or different, chosen from halogen, hydroxy, acyloxy, cycloalkyl, cycloalkenyl, phenyl, cyano, nitro, carboxy or alkoxycarbonyl, nitrogen heterocycle, oxygenated or saturated or unsaturated sulfur containing 5 or 6 members.

In a more concrete aspect the invention is directs to the intermediates of formula I where

R1, R2, R4 and R7 are independently select between H or a linear alkyl radical or branched,

R 3 and R 6 are selected from H or the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more identical or identical substituents. different, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl , cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono amine (-NHR) or disubstituted (-NRR '), monocarboxamide mono (CONHR) or disubstituted (-CONRR'), mono urea (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), any of said cyclic radicals possibly being modified by one or several substitutes. identical or different listeners, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR) , acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate
(-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenated, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members ;

R 5 is selected from the structures of general formula (II) or (III)

5

wherein Z is selected from H, Li, Na, K, N- methylglucosamine, benzyl or tert-butyl ( t- Bu);

X is selected from amide (-CONH- or -NHCO-), ester (-COO- or -OCO-), ether (-O-), thioethers (-S-), disulfide (-SS-), or general formula IV connectors or formula connectors general IV

6

where Ar represents a group mono or bicyclic aryl, or nitrogenous, oxygenated heteroaryl or sulphides containing 5 or 6 members;

m, n, p and q are whole numbers selected from independently between 0, 1, 2, 3,4 or 5;

A, B and D are alkyl substituents.

In an even more concrete aspect the invention It is directed to the compounds of formula I:

- where A, B and D are -CH_ {2} -, X is a amide (-CONH-), m is 0, n and p are 2, q is 1, R1, R3 and R 6 are Me, R 2 and R 4 are H, R 5 is the structure II, where Z is tert-butyl, or

- where A, B and D are -CH_ {2} -, X is a amide (-CONH-), m is 0, n and p are 2, q is 1, R2, R3 and R 6 are Me, R 1 and R 4 are H, R 5 is the structure II, where Z is tert-butyl, or

- where A, B and D without -CH_ {2} -, X is a amide (-CONH-), m is 0, n and p are 2, q is 2, R2, R3, and R 6 are Me, R 1 and R 4 are H, R 5 is the structure II, where Z is tert-butyl.

The compounds of formula I are intermediate useful in the preparation of the compounds of formula VI.

In another aspect the invention is directed to the compounds of general formula VI

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7

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his racemic mix, each of his enantiomers, their diastereomers or their pharmaceutically salts acceptable, in where

R1 is selected from H or the radicals linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl, where each of these radicals is optionally substituted by one or more substituents, identical or different, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONR2), amine (-NH2), mono (-NHR) or disubstituted amine (-NRR '), mono (-CONHR) or disubstituted (-CONRR') carboxyamide, urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONRR '), aminocarbonoyl (-NRCOOR'), aryl, bicycles, heterocyclic nitrogen, oxygenated or saturated or unsaturated sulphide saturated containing 5 or 6 members;

R 2 and R 4 is selected from H or the linear or branched alkyl, linear or branched alkenyl radicals, where each of these radicals is optionally substituted by one or more identical or different substituents, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy
(-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (- NH2), mono (-NHR) or disubstituted (-NRR '), monocarbonamide (CONHR) or disubstituted (-CONRR'), mono urea (-NHCONHR), di (-NRCONHR or -NHCONRR '), or trisubstituted (-NRCONR '
R ''), aminocarbonoyl (-NRCOOR '), aryl, bicyclo, nitrogen heterogenated, oxygenated or saturated or unsaturated sulphide containing 5 or 6 members;

R 3 is selected from H or the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more identical or different substituents, independently chosen from halogen , hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN) , nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR' amine) ), monocarbonamide mono (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR' or -NHCONRR '), or trisubstituted (-NRCONR'R''), aminocarbonoyl (-NRCOOR') , mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), any of said cyclic radicals possibly being modified by one or more substituents, identical or different, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate
(-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenated, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members ;

q is an integer selected in a way independent between 0, 1, 2, 3, 4 or 5;

thus the number of amino acids that constitute the cyclopeptide is variable according to the value of q; Likewise depending on the value of q there will be a variable number of substituents R6, which will be independently selected from

H or the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more identical or different substituents, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy
(-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (- NH 2), mono (-NHR) or disubstituted (-NRR '), monocarbonamide (CONHR) or disubstituted (-CONRR'), mono urea (-NHCONHR), di (-NRCONHR 'or -NHCONRR') amine , or trisubstituted (-NRCONR '
R ''), aminocarbonoyl (-NRCOOR '), mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), any of said cyclic radicals possibly modified by one or more substituents, identical or different, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy ( -OCOR), acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate
(-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenous, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members;

R 8 is one of the polyethylene derivatives cyclic or acyclic of general formula (VII) or (VIII)

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8

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in which Z may be H, Li, Na, K, N- methylglucosamine; and Ln + 3 can be Gd, Eu, Tb, Dy, Ho, Er, Tm and Yb,

X represents a group selected from amides (-CONH- or -NHCO-), amines (-NR-), esters (-COO- or -OCO-),
ethers (-O-), thioethers (-S-), disulfides (-SS-), ureas (-NHCONH-), carbamates (-NHCOO- or -OCONH-), mono- or bicyclic aryls or heteroaryls nitrogen, oxygenated or sulphurated , saturated or unsaturated containing 5 or 6 members, or connectors of general formula IV

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9

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where Ar represents a group mono or bicyclic aryl, or nitrogenous, oxygenated heteroaryl or sulphides containing 5 or 6 members;

m, n, p and q are whole numbers selected from independently between 0, 1, 2, 3, 4 or 5;

A, B, D, are each independently selected from the atoms of nitrogen (N), sulfur (S), oxygen (O) or carbon (C); if said atoms are N or C, they are optionally substituted by one or more substituents, identical or different, independently chosen from hydrogen, halogen, hydroxy (-OH), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR ), amine (-NH2), mono (-NHR) or disubstituted (-NRR '), monocarbonamide (CONHR) or disubstituted (-CONRR'), mono urea (-NHCONHR), di (-NRCONHR ') or -NHCONR'R ''), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), aryl, bicyclo, nitrogen heterogenated, oxygenated or sulphured, saturated or unsaturated containing 5 or 6 members, radicals linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl, any of said radicals possibly being substituted by one or more substituents, identical or different, chosen from the halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkyl, cycloalkenyl , phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate
(-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenous, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members;

m is an integer selected in a way independent between 0, 1, 2, 3, 4 or 5; there are as many R 7 as the value that adopts m, said R 7 are selected so independent between H or linear or branched alkyl radicals, linear or branched alkenyl, any one of which may be radicals eventually substituted by one or more substituents, identical or different, chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR ') amine, monocarboxyamide mono (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR or -NHCONRR '), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), aryl, bicycles, heterocyclic nitrogen, oxygenated or saturated or unsaturated sulphide saturated containing 5 or 6 members;

R, R 'and R' 'can be selected so independent between hydrogen or linear alkyl radicals or branched, linear or branched alkenyl, linear alkynyl or branched, cycloalkyl, cycloalkenyl, bicycloalkyl, mono or bicycloaryl, saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S); being able be any of said radicals eventually substituted by one or more substituents, identical or different, chosen from halogen, hydroxy, acyloxy, cycloalkyl, cycloalkenyl, phenyl, cyano, nitro, carboxy or alkoxycarbonyl, nitrogen heterocycle, oxygenated or saturated or unsaturated sulfur containing 5 or 6 members.

In another particular aspect the invention is directs to the compounds of formula VI wherein R 1, R 2, R 4 and R 7 are independently selected from H or a linear or branched alkyl radical,

R 3 and R 6 are selected from H or the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more identical or identical substituents. different, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl , cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono amine (-NHR) or disubstituted (-NRR '), monocarboxamide mono (CONHR) or disubstituted (-CONRR'), mono urea (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), any of said cyclic radicals possibly being modified by one or several substitutes. identical or different listeners, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR) , acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate
(-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenated, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members ;

R 8 is selected from the structures of general formula (VII) or (VIII)

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10

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wherein Z is selected from H, Li, Na, K, N- methylglucosamine;

X is selected from amide (-CONH- or -NHCO-), ester (-COO- or -OCO-), ether (-O-), thioethers (-S-), disulfides (-SS-), or general formula IV connectors or formula connectors general IV

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eleven

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where Ar represents a group mono or bicyclic aryl, or nitrogenous, oxygenated heteroaryl or sulphides containing 5 or 6 members;

m, n, p and q are whole numbers selected from independently between 0, 1, 2, 3, 4 or 5;

A, B and D are alkyl substituents.

Ln is Gd, Eu, Tb, Dy, Ho, Er, Tm and Yb.

In another more particular aspect the invention is directs compounds of formula VI:

- where A, B and D are -CH_ {2} -, X is a amide (-CONH-), m is 0, n and p are 2, q is 1, R1, R3 and R 6 are Me, R 2 and R 4 are H, R 8 is the structure II, where Z can be H, Li, Na, K, or N-methylglucosamine and the lanthanide Ln3 + are select between Gd, Eu, Tb, Dy, Ho, Er, Tm and Yb, or

- where A, B and D are -CH_ {2} -, X is a amide (-CONH-), m is 0, n and p are 2, q is 1, R2, R3 and R 6 are Me, R 1 and R 4 are H, R` {8 is the structure II, where Z can be H, Li, Na, K, or N-methylglucosamine and the lanthanide Ln3 + are select between Gd, Eu, Tb, Dy, Ho, Er, Tm and Yb, or

- where A, B and D are -CH_ {2} -, X is a amide (-CONH-), m is 0, n and p are 2, q is 2, R2, R3 and R 6 are Me, R 1 and R 4 are H, R 8 is the structure II, where Z can be H, Li, Na, K, or N-methylglucosamine and the lanthanide Ln3 + are select between Gd, Eu, Tb, Dy, Ho, Er, Tm and Yb.

The formula I cyclopeptides and cyclopeptides of formula VI possess the ability to self assemble to give rise to tubular structures due to the formation of hydrogen bonds between the carbonyls of a cyclopeptide and the NH of the amide groups of another cyclopeptide.

In addition, according to the selected substituents, we can have different tubular structures, so that when R 1 is H and R 2 is a substituent selected from the linear or branched alkyl radicals, linear or branched alkenyl, linear or branched alkynyl, where each of these radicals is optionally substituted by one or more substituents, identical or different, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy ( -OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR ' ), amine (-NH2), mono (-NHR) or disubstituted (-NRR '), monocarbonamide (CONHR) or disubstituted (-CONRR'), mono urea (-NHCONHR), di (-NRCONHR ') or
-NHCONRR '), or trisubstituted (-NRCONR'R''), aminocarbonoyl (-NRCOOR'), mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S) , we will have a nanotube formed by two cyclopeptides through an interaction that we will call gamma (γ- γ) (Figure 1, in which the different R groups have been omitted for simplicity).

When R 2 is H and R 1 is a substituent selected from the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more substituents , identical or different, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR ), cycloalkenyl, cyano (-CN), nitro
(-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono amine
(-NHR) or disubstituted (-NRR '), monocarboxyamide (CONHR) or disubstituted (-CONRR'), mono urea (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), we will have a nanotube formed by two cyclopeptides through an interaction that we will call alpha (α- α) (Figure 2, in which the different R groups have been omitted for simplicity).

In the case that both R1 and R2 let H be obtained a tubular structure formed by multiple cyclopeptides (Figure 3, in which the different R groups have omitted for simplicity).

The tubular nature of the ligands cyclopeptide is a very important feature since it allows distinguish between turbulent and laminar flow, thus improving the efficacy of ACs for use in MRI.

In another aspect the invention is directed towards a procedure for obtaining the compounds of formula VI, which comprises the reaction of a compound of general formula I and a lanthanide chloride in water.

Obtaining the compounds of formula general I can be done by coupling between the compound of formula (IX) and the ligand type (II) or the ligand type (III),

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12

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where Y is selected from carboxylic acid, amine, alcohol, thiol, azide, terminal alkene, terminal haluroalkene, terminal alkyne, monocyclic aryl halide or bicyclic, saturated cyclic mono or bicyclic haloheterocycle or unsaturated; Y 'represents a group selected from acids carboxylic, amines, alcohols, thiols, azides, alkenes terminals, haluroalkenes terminals, alkynes terminals, halides monocyclic or bicyclic aryl, monocyclic haloheterocycles or saturated or unsaturated bicyclics; Y and Y 'are selected so that their reactivities allow to form a covalent bond between they.

Finally, the invention is directed towards the use of the compounds of formula VI in the manufacture of Contrast for Magnetic Resonance Imaging (IMR) in the clinical diagnosis

It also targets a pharmaceutical composition comprising a compound of formula VI and at least one excipient or pharmaceutically acceptable vehicle.

And it is directed towards a method for diagnosis of atherosclerosis by IMR in a mammal, which comprises administer to a mammal that needs an effective amount of a compound of formula VI.

The following examples illustrate the present invention and should not be considered limiting thereof.

Embodiment of the invention

Compound 10 was prepared by coupling between cyclopeptide 11 and aminoester 12 using DIC and DMAP in DMF as solvent, and subsequent deprotection of tert- butyl esters in acidic medium (scheme
one).

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Scheme one

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13

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The synthesis of hexapeptide 11 has been carried out following the general procedure known for solid phase synthesis of linear peptides using Fmoc- / t Bu groups as protection groups (scheme 2). It begins with the anchoring of the ( 1S, 3R ) -3 - [(9 H -fluoren-9-ylmethoxycarbonyl) -methyl-amino) -cyclopentanecarboxylic acid, (Fmoc-Me N-Acp), previously prepared, to the 2-chlorotrityl resin (GL BIOCHEM 100-200 mesh, 1% DVB, 1 mmol / g), selective deprotection of the amino terminal group, followed by coupling with L-Fmoc-Ala leading to a dipeptide, which by successive Fmoc couplings - Me-N-Acp-OH, L-Fmoc-Ala-OH, Fmoc-Me N-Acp-OH, and L-Fmoc-Glu (tBu) -OH gave rise to the L-Glu hexapeptide ( O t Bu) - (1 S , 3 R ) - Me N-Acp-L-Ala- (1 S , 3 R ) - Me N-Acp-L-Ala- (1 S , 3 R ) - Me N-Acp. Subsequently, cyclization of the linear hexapeptide was carried out in the presence of TBTU and DIEA in dichloromethane giving rise to cyclopeptide 13 which, by treatment in a strong acid medium (TFA: CH 2 Cl 2), led to cyclopeptide 11
wanted.

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Scheme 2

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14

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(1 S , 3 R ) -Fmoc - Me N-AcpOH has been prepared from Vince's lactam, by acidic hydrolysis to give cis-4-aminocyclopent-2-enocarboxylic acid hydrochloride, which we treat with Boc 2 O in the presence of base, obtaining the corresponding racemic mixture of N-Boc- cis- 4-aminocyclopent-2-enocarboxylic acid. This racemic mixture was resolved by crystallization (+) - phenylethylamine, so that after three crystallizations we obtain the 2 enantiomers of the amino acid with an enantiomeric excess greater than 98%. The (1 R , 4 S ) -N-tert-butoxycarbonylaminocyclopent-2-enocarboxylic acid was reduced with Pd / C under H 2 atmosphere, the reduced amino acid was treated with NaH and MeI to obtain the N-methyl amino acid, the The last step is the deprotection of the amino group in an acid medium and subsequent treatment with 9-fluorenylmethoxycarbonyl chloride, obtaining (1 S , 3 R ) -Fmoc-Me N-Acp properly protected and with the appropriate stereochemistry (scheme 3) .

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Scheme 3

fifteen

On the other hand, the preparation of 12 has been carried out from bis ( tert- butoxycarbonylamino) diethylenetriamine 14 as indicated in scheme 4. Alkylation of 14 with N - (2-bromoethyl) phthalimide leads to 15; Treatment of said compound with trifluoroacetic acid (TFA) in dichloromethane, alkylation with tert - butyl bromoacetate and subsequent treatment with hydrazine in ethanol gives rise to amine 12.

Scheme 4

16

Once the compound 10 has been synthesized it has conducted an NMR study that shows that cyclopeptide 10 is capable of self-assembly, through links hydrogen between the CO groups of one of the sub-units and the NH of another cyclopeptide, giving Place to stable dimers. In addition, computational calculations made, both in the gas phase and in solution in water, confirm the observed self-assembly.

The corresponding lanthanide complexes are obtained by reaction between equimolecular amounts of
MCl 3 • 6 H 2 O (M = lanthanide) and the corresponding organic ligand in aqueous solution at room temperature at a pH between 5-7.

These complexes have a structure suitable, tubular in nature, which gives them some properties anisotropic magnetic

The second example, peptide 16, was prepared by condensation of amine 12 with cyclopeptide 17, which after subsequent treatment with trifluoroacetic acid gave place to the desired cyclohexapeptide (scheme 5).

Scheme 5

17

For the preparation of 17, a solution strategy based on the formation of the Boc- (1 S , 3 R ) -Acp-Me Ala-OFm and Boc- (1 S , 3 R ) dipeptides was selected in this case -Acp-Glu (OBn) -OFm, as shown in scheme 6. The subsequent formation of the Boc tetrapeptide - [(1 S , 3 R ) -Acp - Me Ala -] 2 OFm by coupling of the Boc- (1 S , 3 R ) -Acp-Me Ala-OH dipeptides (obtained by treatment with piperidine) and NH 3 - (1 S , 3 R ) -Acp-Me Ala-OFm (after treatment with TFA), followed by coupling with Boc-Acp-Glu (OBn) -OH, after treatment with TFA led to the corresponding hexapeptide. Cyclization and subsequent deprotection of the glutamic side chain by hydrogenolysis gave rise to peptide 17.

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Scheme 6

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18

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The third example, peptide 21, was prepared by condensation of amine 12 with cyclopeptide 22, which after subsequent treatment with trifluoroacetic acid gave place to the desired cyclohexapeptide (scheme 7).

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Scheme 7

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19

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For the preparation of 22, a solution strategy based on the formation of the Boc- (1 S , 3 R ) -Acp-Me Ala-OFm and Boc- (1 S , 3 R ) dipeptides was selected in this case -Acp-Glu (OBn) -OFm, as shown in Scheme 8. The subsequent formation of the Boc tetrapeptide - [(1 S , 3 R ) -Acp - Me Ala -] 2 OFm by coupling of the Boc- (1 S , 3 R ) -Acp-Me Ala-OH dipeptides (obtained by treatment with piperidine) and NH 3 - (1 S , 3 R ) -Acp-Me OF-Ala (after treatment with TFA). On the other hand, the tetrapeptide Boc- (1 S , 3 R ) -Acp-Me Ala- (1 R , 3 R ) -Acp-Glu (OBn) -OFm was synthesized by coupling of the Boc- (1 dipeptide) S , 3 R ) -Acp-Me Ala-OH (obtained by treatment with piperidine) and H 3 N-Acp-Glu (OBn) -OFm (after treatment with TFA). The coupling of both tetrapeptides, after being treated with piperidine and another TFA, gave rise to the linear octapeptide. Cyclization and subsequent deprotection of the glutamic side chain by hydrogenolysis gave rise to peptide 22.

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Scheme 8

twenty

The corresponding lanthanide complexes are obtained by reaction between equimolecular amounts of
MCl 3 • 6 H 2 O (M = lanthanide) and the corresponding organic ligand in aqueous solution at room temperature at a pH between 5-7.

These complexes have a structure suitable, tubular in nature, which gives them some properties anisotropic magnetic

Synthesis of the compound 10

Cis -4-Aminocyclopent-2-enocarboxylic acid

A solution of Vince's lactam (25 g, 22.9 mmol) in an aqueous solution of HCl (10%, 1.5 L) was kept under stirring at room temperature for 24 h. The solvent was then concentrated under reduced pressure and acetone was added. The solid formed was filtered and washed repeatedly with acetone to obtain 37 g of cis- 4-aminocyclopent-2-enocarboxylic acid as a brown solid, which was used in the next synthesis step without prior purification. 1 H NMR (D 2 O, 250.13 MHz) δ 2.1 (dt, 1H, CHH), 2.70 (dt, 1H, CHH), 3.76 (s, 1H, CH), 4.42 (t, 1H , CH), 6.9-6.25 (dd, 2H, CH = CH); 13 C NMR (D 2 O, 62.83 MHz) δ 31.6 50.1, 56.5, 130.0-136.6, 177.7. MS (Iq) [m / z (%)]: 128 ((M + H) +, 82), 111 (((M + H) + - OH), 53), 110 ((M + -OH), 100 ), 82 ((M + -COOH), 50).

N- Bac- cis- 4-aminocyclopent-2-enocarboxylic acid

To a solution of cis -4-aminocyclopent-2-enocarboxylic acid (37 g, 226.37 mmol) in water (750 mL) and dioxane (750 mL), Boc2O (74.02 g, 339.55 mmol) was added and DIEA (118.6 mL, 679.10 mmol) and the reaction mixture was kept under stirring at room temperature for 3 h. Then, the reaction mixture was acidified to pH = 3 with an aqueous solution of HCl (10%) and extracted with CH2Cl2 (3 x 200 mL). The combination of the organic phases was dried with anhydrous sodium sulfate, the desiccant was removed by filtration and then the solvent was removed under reduced pressure. The yellow oil obtained is purified by crystallization in a mixture of hexane: CHCl 3 (1: 1) to obtain N- Bac- cis- 4-aminocyclopent-2-enocarboxylic acid (41.91 g, 81%). 1 H-NMR (CDCl 3, 250.13 MHz) δ 1.42 (s, 9H, (CH 3) 3 C), 1.9 (s, 1H, CHH), 2.50 (s, 1H, CHH), 3.46 (s, 1H, CH), 4.76 (t, 1H, CH), 5.90 (d, 2H, CH = CH), 10.76 (s, 1H, OH); 13 C-NMR (CDCl 3, 62.83 MHz) δ 28.3, 34.2, 49.2, 55.9, 79.6, 130.1-135.9, 155.3, 178.9. MS (Iq) [m / z (%)]: 228 ((M + H) +, 60), 171 (((M + H) + - C- (CH 3) _ {3}, 100), 127 ((M + H) + - Boc), 52), 110 ((M + - OH), 66). HRMS (EIS) [MH] + calculated for C 11 H 17 NO 4: 228.1158; found 228.1238.

Resolution of N- Bac- cis- 4-aminocyclopent-2-enocarboxylic acid

To a solution of Bocγ-Ace (40.0 g, 176.21 mmol) in CHCl3 (900 mL) was added (-) - 1-phenylethylamine (13.91 mL, 105.7 mmol) and hexane (900 mL) and The mixture was allowed to stand at room temperature for 96 h. Then, the white crystals formed were filtered and washed with hexane. Then, the solid obtained was suspended in CH2Cl2 (500 mL) and washed with 5% hydrochloric acid (3 x 150 mL). The combination of the organic phases was dried with anhydrous sodium sulfate, the desiccant was removed by filtration and finally the solvent was removed under reduced pressure to obtain the acid (1 R , 4 S ) -aminocyclopent-2-enocarboxylic acid (15.95 g; ee = 98%) [α] D 298 = -46.05. 1 H NMR (CDCl 3, 250.13 MHz) δ 1.43 (s, 9H, (CH 3) 3 C), 1.85-253 (m, 2H, CH 2), 3.48 (s, 1H, CH), 4.58-4.89 (t, 1H, CH), 5.88-6.22 (d, 2H, CH = CH), 10.4 (s, 1H, COOH); 13 C NMR (CDCl 3, 62.83 MHz) δ 28.8, 33.8, 49.6, 56.3-57.3, 80.4-81.3, 131.3-135.3, 155.7-157.2, 178-09-179.3. MS (Iq) [m / z (%)]: 228 ((M + H) +, 60), 171 (((M + H) + - C- (CH 3) _ {3}),
100), 127 ((M + H) + - Boc), 52), 110 ((M + - OH), 66). HRMS (EIS) [MH] + calculated for C 11 H 17 NO 4 is 228.1158; found 228.1238.

N-Boc- (1 S , 3 R ) -aminocyclopentanecarboxylic acid ((+) - Boc-Acp-OH)

To a solution of Boc- (1 R , 4 S ) -aminocyclopent-2-enocarboxylic acid (4.8 g; 21.15 mmol) in EtOH (40 mL) was added 10% Pd / C (0.25 g), and the mixture The reaction was maintained with stirring at room temperature, under argon, for 24 hours. Subsequently, the reaction crude was filtered over celite, and the solvent was removed under reduced pressure, obtaining (1S, 3R) -aminocyclopentanecarboxylic acid (4.84 g; 100%). [α] D = - 16.8 (c = 1.0, MeOH). 1 H NMR (CDCl 3, 250.13 MHz) δ 1.37 (s, 9H, 3 x (CH 3) 3), 1.90 (m, 2H, CH 2), 2.19 (m, 2H, CH2), 2.80 (m, 1H, .CHH), 3.83 (s, 1H, CHH), 3.98 (s, 1H, CH), 4.86 (s, 1H, CH), 6.30 ( s, 1H, NH), 10.20 (s, 1H, COOH); 13 C NMR (CDCl 3, 62.83 MHz) δ 28.5, 28.8, 33.6, 36.5, 42.2, 52.4, 156.0, 182.4. MS (Iq) [m / z (%)]: 230 ((M + H) +,
1), 174 ((((M + H) + - C (CH 3) 3), 45), 130 ((M + H) + - Boc), 100), 112 ((M + - OH), 88). HRMS (EIS) [MH] + calculated for C 11 H 20 NO 4 230.1392; found 230.1403.

(1 S , 3 R ) -3-Amino- N - tert -butyloxycarbonyl- N -methylcyclopentanecarboxylic acid ((+) - Boc-Me N-Acp-OH)

To a solution of Boc- (1 S , 3 R ) -3-amino- N - tert -butyloxycarbonyl- N- cyclopentanecarboxylic acid (2.3 g; 10.04 mmol) in dry THF (230 mL), NaH (2 g) was added ; 50.22 mmol) and the reaction mixture was kept under stirring at 0 ° C for 30 min. Then, methyl iodide (3.13 mL; 50.22 mmol) was added, and the resulting mixture was kept under stirring at room temperature overnight. Then, it was hydrolyzed with water and the solvent was removed under reduced pressure. The aqueous solution was washed with Et 2 O, and acidified with a 10% aqueous HCl solution to pH 3. Finally, it was extracted with CH 2 Cl 2. The combination of the organic phases was dried over anhydrous Na 2 SO 4, the desiccant was removed by filtration and the solvent under reduced pressure to obtain the acid (1 S , 3 R ) -3-amino- N - tert - butyloxycarbonyl- N- methylcyclopentanecarboxylic acid (1.42 g, 98%). 1 H NMR (CDCl 3, 250.13 MHz) δ 4.47 (m, 1H, CH), 2.77 (m, 1H, CH), 2.69 (s, 3H, N-CH 3), 2.13 -1.64 (m, 6H), 1.47 (s, 9H); 13 C NMR (CDCl 3, 62.90 MHz) δ 181.2, 155.8, 79.6, 55.8, 41.2, 31.7, 28.3, 28.2, 27.3, 27.2; MS (Iq) [m / z (%)]: 244 ([MH] +, 3), 188 (36), 170 (30), 144 ([MH -Boc] +, 100) , 126 (85), 112 (9); HRMS [MH] + calculated for C 12 H 22 NO 4 244.1549, found 244.1553.

(1 S , 3 R ) -3- N - (9 H -fluoren-9-ylmethoxycarbonyl- N -methyl-cyclopentanecarboxylic ((+) - Fmoc - Me N-Acp-OH)

To a solution of Boc- (1 S ,, 3 R ) -3-amino- N - tert -butyloxycarbonyl- N- methylcyclopentanecarboxylic acid (2.08 g; 8.58 mmol) in CH2Cl2 (10 mL), TFA (10 mL) was added and the reaction mixture was kept under stirring at a temperature of 30 min. Then, the solvent was removed under reduced pressure.

To a solution of the residue obtained in dioxane: H2O (100 mL), FmocCl (2.8 g, 11.1 mmol) was added and the reaction mixture was kept under stirring for 15 min. Next, Na 2 CO 3 (2.73 g, 25.74 mmol) was added and the reaction mixture was kept under stirring for 12 h. Then, the reaction crude was acidified with a 5% aqueous HCl solution and extracted with CH2Cl2. The combination of the organic phases was dried with Na2SO4, the desiccant was removed by filtration and the solvent under reduced pressure. The reaction crude was purified by column chromatography on silica gel using as eluent a MeOH / CH2Cl2 mixture (gradient 0-5%). 1 H NMR (CDCl 3, 250.13 MHz) δ 2.15-1.62 (m, 6H, CH 2), 2.81 (s, 3H, N-CH 3), 2.83 (m, 1H , C H COOH), 4.25 (t, 1H, O-CH 2 C H ), 4.44 (d, 2H, OC H 2 CH), 4.62 (wide s, 1H, CH-N), 7.29 -7.43 (m, 4H), 7.58 (d, 2H), 7.77 (d, 2H) ppm.

Cycle - [((1S, 3R) - Me N-Acp-L-Ala] 2 - ((1 S, 3 R) - Me N-Acp-L-Glu (OtBu))] (13)

The coupling of Fmoc - Me N-Acp (0.313 g, 0.855 mmol), with the 2-chlorotrityl resin (0.285 g, 0.285 mmol Cl) was carried out in the presence of DIEA (0.368 g, 2.85 mmol) in CH 2 Cl 2 for 2 h.

Selective unprotections of groups Fmoc terminals of the resin-bound amino acids were carried carried out using 20% piperidine in DMF.

Fmoc- N- amino acid couplings have been made by activation with HATU, if the amino acid anchored in the resin is N- methylated, and with HBTU in the presence of DIEA in DMF, following the usual procedures.

Hexapeptide release from the resin was performed in a mixture of acetic acid / trifluoroethanol / dichloromethane (1: 1: 8). The linear hexapeptide L-Glu (O t Bu) - (1 S , 3 R ) - Me N-Acp-L-Ala- (1 S , 3 R ) - Me N-Acp -L-Ala- (1 S , 3 R ) - Me N-Acp was cyclized with TBTU in the presence of DIEA in CH 2 Cl 2. Compound 13 was purified by HPLC (Phenomenex Maxsil-10 silica column 250x10.00 mm). Finally, the solvent was removed under reduced pressure to obtain cyclopeptide 12 as a white solid (30 mg, 15%) 1 H NMR (CDCl 3, 250.13 MHz) δ 1.32 (d. 6H, 2 x CHC H 3), 1.41 (s, 9H, (CH 3) 3 C), 1.50-2.44 (5m, 22H, CH 2), 2.92 (m, 3H, C H COO-NH), 3.03 (3s, 9H, 3 x N-CH3), 4.78 (m, 3H, C H -NH-CO), 5.15 (m, 3H, NC H -CO), 8.22 (3m , 3H, NH) ppm.

Cycle - [((1S, 3R) - Me N-Acp-L-Ala) 2 ((1 S, 3R) - Me N-Acp-L-Glu)] (eleven)

A solution of 13 (30 mg, 0.042 mmol) in 0.8 mL of TFA / CH2Cl2 (1: 1) was kept under stirring at room temperature for 1 h. The solvent was then removed under reduced pressure to obtain compound 11 as a white solid. 1 H NMR (CDCl 3, 250.13 MHz) δ 1.33 (d, 6H, 2 x CHC H 3), 1.48-2.48 (4m, 22H, CH 2), 2.92 (m , 3H, C H -CO-NH), 3.02 (s wide, 12H, 3 x N-CH3 and C H -CO-NH), 4.74 (m, 3H, C H -NH-CO), 5.20 (m, 3H, NH-C H -CO), 8.58 (m, 3H, NH) ppm.

(2 - {(2- tert -Butoxycarbonylaminoethyl) - [2- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -ethyl] -amino} -ethyl) -carbonate of tert -butyl (15)

A solution of 14 (1.42 g, 4.68 mmol), N - (2-bromoethyl) phthalimide (1.29 g, 5.08 mmol) and Na2CO3 (1.08 g, 10.16 mmol) in dry acetonitrile (30 mL) was maintained under stirring at reflux for 48 h. The solid was then filtered in suspension and the solvent was removed under reduced pressure. The reaction crude was purified by column chromatography on silica gel using as eluent a mixture of CH2Cl2 / EtOH (96: 4), the product being obtained as a white solid (mp 121-122 ° C). , CH 2 Cl 2 / Hexane); 1 H NMR (CDCl 3, 400 MHz) δ 1.40 (s, 18H, (CH 3) 3 C), 2.61 (t, 4H, NC H 2 -CH_ {2 -NHBoc), 2.75 (t, 2H, (CO) 2 N-CH 2 -C H 2 -N), 3.13 (m, 4H, C H 2 - NHBoc), 3.74 (t, 2H, (CO) 2
N-CH2), 4.97 (broad s, 1H, NHBoc), 7.72 (m, 2H, aromatic), 7.85 (m, 2H, aromatic) ppm; 13 C NMR (CDCl 3, 400 MHz): δ 28.0, 35.8, 37.9, 52.0, 53.2, 78.5, 122.9, 131.5, 133.6, 155.6, 168.0 ppm; IR (ATR): 33 3361.6, 1704.4, 1683.0, 1522.3, 1164.5, 1014.7, 869.8, 723.5 cm -1; Anal. Calcdo for C_ {24} H_ {36} N_ {O} {{}}: C 59.27, H 9.24, N 16.46. Found C 59.30, H 9.00, N 16.46.

[(2 - {(2-Aminoethyl) - [2- (bis- tert -butioxicarbonilmetilamino) ethyl] amino} ethyl) - tert -butoxicarbonilmetilamino] ethyl tert - butyl (12)

A solution of 15 (0.72 g, 1.5 mmol) in a mixture of TFA / CH 2 Cl 2 (1: 1) (22 mL) was kept under stirring at room temperature for 24 h and then the solvent was removed at reduced pressure The obtained residue was dissolved in dry acetonitrile (30 mL), tert- butyl bromoacetate (1.29 g, 6.6 mmol) and K 2 CO 3 (2.05 g, 14.83 mmol) were added and the reaction mixture was kept at reflux for 24 h. The reaction crude was then allowed to cool and the solvent was removed under reduced pressure. The crude obtained was dissolved in dry ethanol (50 mL), excess hydrazine monohydrate was added and the reaction mixture was kept under stirring at reflux for 4 hours. The solid formed was then filtered and the solvent removed under reduced pressure. The reaction crude was purified by column chromatography on silica gel using as eluent a CH 2 Cl 2 / MeOH mixture with a gradient of 7.5 to 12%. Product 12 was obtained as a yellow oil. 1 H NMR (CDCl 3, 400 MHz) δ 1.45 (s, 36H, 4 x (CH 3) 3 C), 2.62 (t, 4H, 2 x C H 2 2 -N), 2.80 (m, 6H, 3 x N-CH 2), 3.07 (t, 2H, C H 2 -NH 2), 3.42 (s, 8H, N-CH_ {2} -CO) ppm; 13 C NMR (CDCl 3, 400 MHz): δ 28.1, 38.1, 48.8, 51.6, 52.5, 55.1, 81.8, 170.7 ppm; IR (ATR): 17 1729.2, 1680.8, 1147.5 cm -1; MS (FAB) [m / z (%)]: 603 (100), 560 (26), 160 (45), 145 (35), 57 (37); HRMS (FAB): [MH] + calculated for C 30 H 58 N 4 O 8: 603.4333, found 603.4320.

Obtaining the cyclopeptide (10)

To a solution of cyclopeptide 11 (27.6 mg, 0.042 mmol), N , N -diisopropylcarbodiimide (DIC) (8 mg, 0.063 mmol) and N , N- dimethylaminopyridine (DMAP) (30.78 mg, 0.252 mmol) in dry DMF (0.5 mL), a solution of 12 (37.64 mg, 0.063 mmol) in dry DMF (0.6 mL) was added under argon, and the reaction mixture was kept under stirring at room temperature, until the total consumption of the product of departure checked by MS (24 h). Finally, the solvent was removed under reduced pressure. The crude obtained is then dissolved in a mixture of TFA / CH2Cl2 in a 1: 1 ratio (1.8 mL) and the reaction mixture is kept under stirring at room temperature for 24 h. Then, the solvent was removed under reduced pressure and the reaction crude was purified by HPLC (Licroscarp C18 column), using H 2 O: TFA (99.9: 0.1) and ACN: TFA (99.9: 0.1) as the mobile phase. . The solution was lyophilized to obtain 10 as a white solid (17 mg, 40%; mp 265-268 ° C). 1 H NMR (D 2 O, 500 MHz): δ 1.27 (d, 6H, CHCH 3), 1.54 (m, 3H, CH 2), 1.80-2.08 (2m, 14H , CH 2 and C H 2 CH 2 CONH), 2.13 (m, 3H, CH 2), 2.24-2.39 (2m, 2H, CH 2 C H 2 CONH ), 2.55-3.43 (6m, 15H), 3.02 (s, 9H, N-CH 3), 3.79 (s, 8H, C H 2 CO 2 H), 4.72-4.89 (m, 6H, CH-N and C H CH 3) ppm. HRMS (ESI-TOF; negative ions): [MH] + calculated for C 46 H 74 N 10 O 15: 1006.534, found 1007.542.

Synthesis of the compound 16

Tert-butyl- (S) -1 - (((9H-fluoren-9-yl) -methoxycarbonyl-3- (phenoxycarbonyl) propylcarbamate ((L) -Boc-Glu (OBz) -OFm)

A solution of Boc-L-Glu (OBz) -OH (1.0 g, 2.96 mmol) in dry CH2Cl2 (60 mL) was treated with EDC • HCl (724 mg, 3.26 mmol), HOBt (500 mg, 3.70 mmol), 9-fluorenyl methanol (642 mg, 3.26 mmol) and DMAP (452 mg, 3.70 mmol). After 4 hours stirring at t. a., washed the solution with HCl (10%), NH4Cl (sat.) and NaHCO3 (sat.). The organic phase was dried with Na2SO4 and concentrated to empty, and the resulting crude was purifiadpo by means of a column chromatography (20% hexane / dichloromethane). 1 H-NMR (CDCl 3, 250.13 MHz) δ: 1.47 (s, 9H), 1.92 (dt, 1H), 2.15 (m, 1H), 2.40 (m, 2H), 4.22 (t, 1H), 4.57-4.38 (m, 3H), 5.15 (s, 2H), 5.19 (d, 1H), 7.44-7.26 (m, 9H), 7.62-7.60 (dd, 2H), 7.77-7.74 (dd, 2H); E.M. (ESI-TOF) [m / z]: 538.2183 (M + Na +), 416.1837 (MH + - Boc). HRMS (ESI-TOF) [MNa] + calculated for C 31 H 33 N 1 Na 1 O 6: 538.2200; found 538.2183.

Acid (2S) -2-amino-N-tert-butyloxycarbonyl-N-methyl-propanoic acid ((L)) - Boc - Me-N-Ala-OH)

To a solution of the amino acid (L) -Boc-Ala-OH (5.0 g; 26.45 mmol) in dry THF (265 mL), NaH (3.17 g; 132.27 mmol) and the reaction mixture was maintained with stirring at 0 ° C for 30 min. Then, methyl iodide was added (8.23 mL; 132.37 mmol), and the resulting mixture was maintained with stirring at room temperature overnight. Then, it was hydrolyzed with water and the solvent was removed at reduced pressure The aqueous solution was washed with Et2O, and was acidified with a 10% aqueous HCl solution to pH 3. Finally, it was extracted with CH2Cl2. The combination of Organic phases were dried over anhydrous Na2SO4, removed the desiccant by filtration and the solvent under reduced pressure obtaining the desired acid (5.36 g, 99%). The resulting product It is an oil. 1 H-NMR (CDCl 3, 250.13 MHz) δ: 1.45 (m, 12H), 2.85 (d, 3H), 4.45 (q, 0.5 H), 4.85 (q, 0.5 H), 10.55 (s, 1H).

(9H-fluoren-9-il) methyl (2S) -2-amino-N-tert-butyloxycarbonyl-N-methyl-propanate ((L) -Boc - Me-N-Ala-OFm)

A solution of Boc-L - Me N-Ala-OH (5.37 g, 26.45 mmol) in dry CH2Cl2 (60 mL) was treated with EDC • HCl (6.47 g, 33.74 mmol), HOBt (4.47 g, 33.06 mmol), 9-fluorenyl methanol (5.73 g, 29.1 mmol) and DMAP (4.04 g, 33.06 mmol). After 4 hours stirring at t. a., I know washed the solution with HCl (10%), NH 4 Cl (sat.) and NaHCO 3 (sat.). The organic phase was dried with Na2SO4 and concentrated under vacuum, and the resulting crude was purified by a column chromatography (10% ethyl acetate / hexane). Getting an oil. 1 H-NMR (CDCl 3, 250.13 MHz) δ: 1.48-1.21 (b, 13H), 2.03 (s, 0.5), 2.76 (d, 3H), 4.59-4.06 (b, 4H), 4.06 (q, 0.5H), 7.42-7.25 (dt, 4H), 7.58 (d, 2H), 7.74 (d, 2H).

Boc- (1S, 3R) -Acp-L - Me-N-Ala-OFm (18)

A solution of Boc - (+) - L - Me N-Ala-OFm (1.66 g, 4.36 mmol) in CH2Cl2: TFA (44 mL) was stirred at room temperature for 15 min, then the solvent under reduced pressure, the residue was dried under vacuum for 3 h. The residue was dissolved in CH2Cl2 (20 mL) and added a suspension of (1S, 3R) -Boc-Acp-OH (998 mg, 4.36 mmol), HATU, (1.82 g, 4.80 mmol), DIEA (4.6 mL, 26.16 mmol) in CH2C12 (20 mL). The mixture was stirred at temperature. ambient for 45 minutes. The solution was washed with HCl (5%) and NaHCO 3 (sat.), The organic phase was dried with Na 2 SO 4 anhydrous, filtered and concentrated. The reaction crude was purified by silica gel column chromatography using as eluent ethyl acetate / hexane (gradient 20% to 30%). Getting a foam white 1 H-NMR (CDCl 3, 250.13 MHz) δ: 1.29 (d, 3H), 1.46 (d, 9H), 2.08-1.56 (b, 6H), 2.43 (s, 0.6H), 2.70 (s, 2.4H), 2.97 (m, 1H), 4.22-3.98 (m, 2H), 4.78-4.38 (m, 2H), 5.18 (q, 1H), 5.55 (dd, 1H), 7.42-7.25 (dt, 4H), 7.58 (dd, 2H), 7.74 (d, 2H). E.M. (ESI-TOF) [m / z]: 515.2499 (M + Na +), 437.2066 (MH + - t Bu), 393.2159 (MH + - Boc). HRMS (ESI-TOF) [MH] + calculated for C 29 H 37 N 2 O 5: 493.2730; found 493.2683.

Boc - [(1S, 3R) -Acp-L - Me-N-Ala] 2 -OFm (19)

A solution of Boc- (1S, 3R) -Acp-L - Me-N-Ala-OFm (600 mg, 1.22 mmol) in CH2Cl2: TFA (12.2 mL) was stirred at room temperature for 15 min., then the solvent under reduced pressure, the residue was dried under vacuum for 3 h, giving rise to salt TFA - - + H 2 N- (1S, 3R) -Acp-L - Me-N-Ala-OFm (room). On the other hand, a solution of Boc- (1S, 3R) -Acp-L - Me-N-Ala-OFm (600 mg, 1.22 mmol) in CH2Cl2 (9.8 mL) with piperidine (2.5 mL), stirred at room temperature, after 20 minutes it was washed with HCl (5%), the organic phase was dried with Na2SO4 anhydrous, filtered, and concentrated, obtaining a foam. This foam it was dissolved in CH2Cl2 (24 mL) and HATU (510 mg, 1.34 mmol), DIEA (0.85 mL, 4.88 mmol), the suspension was stirred for 2 minutes and salt A was added. The mixture was stirred at room temperature for 45 minutes. The solution was washed with HCl (5%) and NaHCO3 (sat.), The organic phase was dried with Anhydrous Na 2 SO 4, filtered and concentrated. The crude of reaction was purified by silica gel column chromatography using CH2Cl2 MeOH as eluent (gradient 1% MeOH to 3%). Getting a white foam. 1 H-NMR (CDCl 3, 250.13 MHz) δ: 1.21-1.46 (m, 16H), 2.08-1.56 (b, 18H), 2.47-3.20 (b, 8H), 2.97 (m, 1H), 4.01-4.78 (m, 3H), 5.00-5.30 (m, 1.5H), 5.86 (d, 0.5H), 7.45-7.28 (dt, 4H), 7.56 (dd, 2H), 7.75 (d, 2H). E.M. (ESI-TOF) [m / z]: 711.3905 (M + Na +), 689.3901 (M + H +), 589.3707 (MH + - Boc). HRMS (ESI-TOF) [MH] + calculated for C 39 H 53 N 4 O 7: 689.3909; found 689.3901.

Boc - [(1S, 3R) -Acp-L-Glu (OBz)] - OFm (twenty)

A solution of Boc- (1S, 3R) -L-Glu (OBz) -OFm (600 mg, 1.17 mmol) in CH2Cl2: TFA (11.6 mL) was stirred at room temperature for 15 min., then the solvent under reduced pressure, the residue was dried under vacuum for 3 h. The residue was dissolved in CH2Cl2 (13 mL) and added a suspension of (1S, 3R) -Boc-Acp-OH (267 mg, 1.17 mmol), HATU, (531 g, 1.40 mmol), DIEA (1.22 mL, 6.99 mmoles) in CH 2 Cl 2 (10 mL). The mixture was stirred at room temperature for 45 minutes. The solution was washed with HCl (5%) and NaHCO3 (sat.), The organic phase was dried with Anhydrous Na 2 SO 4, filtered and concentrated. The crude of reaction was purified by silica gel column chromatography using as CH 2 Cl 2: MeOH (gradient 1% MeOH to 3%). Getting a white foam. 1 H-NMR (CDCl3, 250.13 MHz) δ: 1.26-1.12 (m, 3H), 1.42 (s, 13H), 2.40-1.60 (b, 16H), .58 (m, 1H), 2.80 (s, 1.5H), 2.96 (s, 0.5H), 3.06 (s, 0.5H), 4.08 (m, 2H), 4.22 (t, 1.4H), 4.54 (d, 2H), 4.60 (m, 1H), 5.12 (s, 2H), 5.77-5.39 (2xb, 1H), 6.23 (d, 1H), 7.43-7.26 (m, 9H), 7.57 (dd, 2H), 7.75 (dd, 2H). E.M. (ESI-TOF) [m / z]: 647.2894 (M + Na +), 627.3081 (M + H <+>), 527.2535 (MH <+> - Boc). HRMS (ESI-TOF) [MH] + calculated for C 37 H 43 N 2 O 7: 627.3065; found 627.3081.

Boc - [((1S, 3R) -Acp-L - Me N-Ala) 2 - (1S, 3R) -Acp-Glu (OBz)] - OFm (twenty-one)

A solution of Boc - [(1S, 3R) -Acp-Glu (OBz)] - OFm (377 mg, 0.60 mmol) in CH2Cl2: TFA (6 mL) was stirred at room temperature for 15 min., then the solvent under reduced pressure, the residue was dried under vacuum for 3 h, giving rise to salt TFA - - + H 2 N - [(1S, 3R) -Acp-L-Glu (OBz)] - OFm (salt B). On the other hand, a solution of Boc - [(1S, 3R) -Acp-L - Me-N-Ala] 2 -OFm (415 mg, 0.60 mmol) in CH 2 Cl 2 (4.8 mL) with piperidine (1.2 mL), stirred at room temperature, after 20 minutes it was washed with HCl (5%), the organic phase was dried with Na 2 So 4 anhydrous, filtered, and concentrated, obtaining a foam. This foam It was dissolved in CH2Cl2 (24 mL) and HATU (252 mg, 0.66 mmol), DIEA (0.63 mL, 3.62 mmol), the suspension was stirred for 2 minutes and salt B was added. The mixture was stirred at room temperature for 45 minutes. The solution was washed with HCl (5%) and NaHCO3 (sat.), The organic phase was dried with Anhydrous Na 2 SO 4, filtered and concentrated. The crude of reaction was purified by silica gel column chromatography using CH2Cl2 as eluent: MeOH (gradient 1% MeOH to 3%). Getting a white foam. 1 H-NMR (CDCl 3, 250.13 MHz) δ: 1.31 (dd, 6H), 1.42 (s, 13H), 2.12-1.60 (b, 28H), 2.24 (q, 2H), 2.63 (b, 0.7H), 2.82 (d, 1H), 2.92 (d, 6H), 3.24 (b, 1.5H), 4.70-3-98 (b, 7H), 5.30-5.01 (b, 3.60H), 5.84 (d, 0.4H), 6.43 (d, 0.6H), 7.48-7.28 (m, 9H), 7.56 (t, 2H), 7.75 (dd, 2H). E.M. (ESI-TOF) [m / z]: 1041.5269 (M + Na +), 1019.5462 (M + H +). HRMS (ESI-TOF) [MH] <+> calculated for C_ {57} H_ {74} N_ {O} {11}: 1019.5488; found 1019.5462.

c - [((1S, 3R) -Acp-L - Me N-Ala) 2 - (1S, 3R) -Acp-Glu (OBz) -] (22)

A solution of hexapeptide 13, Boc - [((1S, 3R) -Acp-L - Me N-Ala) 2- (1S, 3R) -Acp-Glu (OBz)] - OFm, (542 mg, 0.553 mmol), in CH2Cl2 (4.2 mL) was treated with piperidine (1.1 mL), this solution was stirred at room temperature for 20 minutes, and washed with HCl (5%), the organic phase was dried with anhydrous Na2SO4, it was filtered and concentrated in vacuo. He residue obtained was dissolved in CH2Cl2: TFA (5.4 mL) and was stirred for 15 minutes at room temperature, after this time the solvent was removed under reduced pressure, and dried at emptied for 3 hours. The resulting hexapeptide was dissolved in CH 2 Cl 2 (533 mL) and treated with PyAOP (333 mg, 0.64 mmol) and DIEA (0.56 mL, 3.20 mmol). The solution was kept low stirring and at room temperature for 12 h, then washed with one HCl solution (5%) and another saturated NaHCO3, the Organic phase was dried with anhydrous Na2SO4, filtered and concentrated. The resulting crude was purified by HPLC-FR, using as eluent H2O: 0.1 TFA (A) and ACN: 0.1 TFA (B), gradient 5% B to 95% B in 30 min. and lyophilisate obtaining a white solid. 1 H-NMR (CDCl 3, 500.13 MHz): 1.36-1.19 (m, 15H), 2.12-1-57 (b, 60H), 2.49-2.28 (m, 5H), 2.73-2.56 (m, 7.5H), 3.20-2.84 (m, 28H), 3.96 (q, 1H), 4.14 (m, 1H), 4.50-4.20 (m, 9H), 4.75 (q, 0.2H), 5.18-5.03 (m, 8H), 6.47 (d, 1H), 6.54 (d, 1H), 6.79 (d, 0.2H), 7.28 (m, 12H), [7.60 (d), 7.65 (d), 7.74 (d), 7.93 (d), 8.02 (d), 8.06 (d), 8.21 (d); 6H].

HRMS (ESI-TOF) [MH] + Calculated for C 38 H 55 N 6 O 8: 723.4076; found 723,4096.

c - [((1S, 3R) -Acp-L - Me N-Ala) 2 - (1S, 3R) -Acp-Glu-] (17)

Cyclopeptide 14 (21 mg, 0.03 mmol) is dissolved in MeOH (2 mL) and Pd / C (4.7 mg, 0.0045 mmol) was added, the resulting suspension was stirred for 3 h under an atmosphere of H2 (g). After this time it was filtered over celite and was dragged with methanol, concentrated in vacuo, obtaining a solid White. 1 H-NMR (CDCl 3, 500.13 MHz): 2.65-0.6 (b, 99H), 2.55 (s, 1H), 2.82-2.64 (m, 2H), 2.88 (s, 3H), 3.06-2.96 (5H), 3.21 (m, 1H), 4.17 (q, 1H), 4.25 (m, 1H), 4.36 (m, 1H), 4.44 (m, 1H), 4.91 (q, 1H), 5.14 (q, 1H), 6.38 (d, 1H), 7.26 (d, 1H), 7.82 (d, 1H), 8.00 (d, 1H).

HRMS (ESI-TOF) [MH] + Calculated for C 31 H 49 N 6 O 8: 633.3606; found 633.3602.

Obtaining the cyclopeptide 16

To a solution of the cyclopeptide 17 (22.9 mg, 0.035 mmol) in dichloromethane (700 µL) and DMF (150 µL), HATU ( O - (7-Azabenzotriazol-1-yl) - N , N , N 'was added , N'- tetramethyluronium hexafluorophosphate) (19.8 mg, 0.052 mmol) and DIEA (36 µL, 0.21 mmol), and stirred for 2 min, then a solution of compound 12 (31.4 mg, 0.052 mmol) in dichloromethane was added (150 µL), and the reaction mixture was kept under stirring at room temperature, until the total consumption of the starting product. The solvent was removed under reduced pressure. Then the crude obtained was dissolved in a mixture of TFA / CH 2 Cl 2 in a 1: 1 ratio (600 µL) and the reaction mixture was kept under stirring at room temperature for 1 h. Then, the solvent was removed under reduced pressure and the reaction crude was purified by HPLC (Licroscarp C18 column), using H 2 O: TFA (99.9: 0.1) and ACN: TFA (99.9: 0.1) as the mobile phase. . The solution is lyophilized to obtain 16 as a white solid (17 mg).

HRMS (ESI-TOF; negative ions): [MH] + calculated for C 45 H 73 N 10 O 15: 993.5256, found 993.52.51.

Boc - [(1S, 3R) -Acp-L - Me-N-Ala- (1S, 3R) -Acp-L-Glu (OBz)] - OFm (2. 3)

A solution of Boc- (1S, 3R) -Acp-L-Glu (OBz) -OFm (764, 1.22 mmol) in CH2Cl2: TFA (12.2 mL) was stirred at room temperature for 15 min., then the solvent under reduced pressure, the residue was dried under vacuum for 3 h, giving rise to salt TFA - - + H 2 N- (1S, 3R) -Acp-L-Glu (OBz) -OFm (room). On the other hand, a solution of Boc- (1S, 3R) -Acp-L - Me-N-Ala-OFm (600 mg, 1.22 mmol) in CH2Cl2 (9.8 mL) with piperidine (2.5 mL), stirred at room temperature, after 20 minutes it was washed with HCl (5%), the organic phase was dried with Na2SO4 anhydrous, filtered, and concentrated, obtaining a foam. This foam it was dissolved in CH2Cl2 (24 mL) and HATU (510 mg, 1.34 mmol), DIEA (0.85 mL, 4.88 mmol), the suspension was stirred for 2 minutes and salt A was added. The mixture was stirred at room temperature for 45 minutes. The solution was washed with HCl (5%) and NaHCO3 (sat.), The organic phase was dried with Anhydrous Na 2 SO 4, filtered and concentrated. The crude of reaction was purified by silica gel column chromatography using CH2Cl2 as eluent: MeOH (gradient 1% MeOH to 3%). Obtaining a white foam (rto .: 82%, 987 mg). HRMS (ESI-TOF) [MH] + calculated for C 47 H 59 N 4 O 9: 822.9848; found 822.9853.

Boc - [((1S, 3R) -Acp-L - Me-N-Ala- (1S, 3R)) 3 -Acp-L-Glu (OBz)] - OFm (24)

A solution of Boc - [(1S, 3R) -Acp-L - Me-N-Ala- (1S, 3R) -Acp-L-Glu (OBz)] - OFm (500 mg, 0.43 mmol) in CH_ {2 Cl2}: TFA (12.2 mL) was stirred at room temperature for 15 min., Then the solvent was removed under reduced pressure, the residue was dried under vacuum for 3 h, giving rise to salt TFA <+> - <2> H2 N - [(1S, 3R) -Acp-L-Me N-Ala- (1S, 3R) -Acp-L-Glu (OBz)] -OFm (salt A). On the other hand, a solution of Boc - [(1S, 3R) -Acp-L-Me-N-Ala] 2 -
OFm (296 mg, 0.43 mmol) in CH2Cl2 (9.8 mL) with piperidine (2.5 mL), stirred at room temperature, after 20 minutes washed with HC1 (5%) , the organic phase was dried with anhydrous Na2SO4, filtered, and concentrated, obtaining a foam. This foam was dissolved in CH2Cl2 (24 mL) and HATU (188 mg, 0.49 mmol), DIEA (0.45 mL, 2.58 mmol) was added, the suspension was stirred for 2 minutes and the salt A. The mixture was stirred at room temperature for 45 minutes. The solution was washed with HCl (5%) and NaHCO3 (sat.), The organic phase was dried with anhydrous Na2SO4, filtered and concentrated. The reaction crude was purified by silica gel column chromatography using CH2Cl2 MeOH as eluent (gradient 1% MeOH to 5%). Getting a white foam. (338 mg, rto: 68%); HRMS (ESI-TOF) [MH] + calculated for C 67 H 91 N 8 O 13: 1215.4773; found 1215.4576.

c - [((1S, 3R) -Acp-L - Me N-Ala) 3- (1S, 3R) -Acp-Glu (OBz) -] (25)

A solution of octapeptide 24, Boc - [((1S, 3R) -Acp-L - Me N-Ala) 3 - (1S, 3R) -Acp-Glu (OBz)] - OFm, ( 100 mg, 0.085 mmol), in CH2Cl2 (0.8 mL) was treated with piperidine (0.2 mL), this solution was stirred at room temperature for 20 minutes, and washed with HCl ( 5%), the organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The obtained residue was dissolved in CH2Cl2: TFA (1.0 mL) and stirred for 15 minutes at room temperature, after this time the solvent was removed under reduced pressure, and dried under vacuum for 3 hours. The resulting octapeptide was dissolved in CH2Cl2 (85 mL) and treated with PyAOP (55.36 mg, 0.106 mmol) and DIEA (89 µL, 0.51 mmol). The solution was kept under stirring and at room temperature for 12 h, then washed with an HCl solution (5%) and a saturated NaHCO3 solution, the organic phase was dried with anhydrous Na2SO4, filtered and concentrated. The resulting crude was purified by HPLC-FR, using as eluent H2O: 0.1 TFA (A) and ACN: 0.1 TFA (B), gradient 5% B to 95% B in 30 min. and lyophilized to obtain a white solid. HRMS (ESI-TOF) [MH] +
Calculated for C 48 H 7 N 8 O 10: 919.1170; found 919.1174.

c - [((1S, 3R) -Acp-L - Me N-Ala) 3 - (1S, 3R) -Acp-Glu-] (26)

Cyclopeptide 25 (26.2 mg, 0.03 mmol) is dissolved in MeOH (2 mL) and Pd / C (4.7 mg, 0.0045 mmol) was added, the resulting suspension was stirred for 3 h under an atmosphere of H2 (g). After this time it was filtered over celite and was dragged with methanol, concentrated in vacuo, obtaining a solid White. HRMS (ESI-TOF) [MH] + calculated for C 41 H 65 N 8 O 10: 828.9945; found 828.9948.

Obtaining the cyclopeptide 21

To a solution of cyclopeptide 26 (23.58 mg, 0.03 mmol) in dichloromethane (700 µL) and DMF (150 µL), HATU ( O - (7-Azabenzotriazol-1-yl) - N , N , N 'was added , N ' -tetramethyluronium hexafluorophosphate) (17.1 mg, 0.045 mmol) and DIEA (31.4 mg, 0.18 moles), and stirred for 2 min, then a solution of compound 12 (27.1 mg, 0.045 mmol) in dichloromethane ( 150 µL), and the reaction mixture was kept under stirring at room temperature, until the total consumption of the starting product. The solvent was removed under reduced pressure. Then the crude obtained was dissolved in a mixture of TFA / CH 2 Cl 2 in a 1: 1 ratio (600 µL) and the reaction mixture was kept under stirring at room temperature for 1 h. Then, the solvent was removed under reduced pressure and the reaction crude was purified by HPLC (Licroscarp C18 column), using H 2 O: TFA (99.9: 0.1) and ACN: TFA (99.9: 0.1) as the mobile phase. . The solution is lyophilized to obtain 21 as a white solid (15.4 mg). HRMS (ESI-TOF) [MH] + calculated for C 55 H 89 N 12 O 17: 1189.3574; found 1189.3577.

Procedure for the synthesis of the Gd (III) complex of ligand 10 : A solution of an equivalent of ligand 10 and an equivalent of GdCl 3 -6H 2 O in 5 mL of water (MQ) at pH 5 5 -7 was kept under stirring at room temperature for 4 h. The solvent was then removed under reduced pressure.

Procedure for the synthesis of the Gd (III) complex of ligand 16 : A solution of an equivalent of ligand 16 and an equivalent of GdCl 3 -6H 2 O in 5 mL of water (MQ) at pH 5 5 -7 was kept under stirring at room temperature for 4 h. The solvent was then removed under reduced pressure.

Procedure for the synthesis of the Gd (III) complex of ligand 21 : A solution of an equivalent of ligand 21 and an equivalent of GdCl 3 -6H 2 O in 5 mL of water (MQ) at pH 5 5 -7 was kept under stirring at room temperature for 4 h. The solvent was then removed under reduced pressure.

Magnetic Resonance Study: relaxivity

Magnetic Resonance studies that are presented in this invention have been performed on a spectrometer of 60 MHz (1.5 T). The longitudinal and transverse relaxation times have been measured at a concentration of 0.5 mM of organic ligand 10 or of the corresponding Gd (III) complex, 150 mM NaCl (ionic strength) and 100 mM TRIS / HC1 using water (MQ) as solvent, at different temperatures.

The relaxivity has been calculated according to the equation represented below:

r_ {1 (2)} = \ Delta [1 / T_ {1 (2)}] / [LGd]

where, r_ {1 (2)} is the longitudinal (transversal) relaxivity, Δ [1 / T_ {1 (2)}] is the difference between the inverse of the Longitudinal (transverse) relaxation times of the corresponding complex of Gd (III) and ligand and, [LGd] is the concentration of the complex of Gd (III) used (equal to the concentration of ligand).

NMR studies have been performed using aqueous solutions of Gd (III) -10 obtaining a relaxing value r_ {1} 2.80 (1.64) and r_ {2} 3.80 (2.31) s -1 mM -1 at 37 ° C, pH ~ 7.2 (25 ° C, pH ~ 7.2).

Magnetic Resonance studies that are presented in this invention have been performed on a spectrometer of 60 MHz (1.5 T). The longitudinal and transverse relaxation times have been measured at a concentration of 0.5 mM of organic ligand 16 or of the corresponding Gd (III) complex, 150 mM NaCl (ionic strength) and 100 mM TRIS / HC1 using water (MQ) as solvent, at different temperatures.

The relaxivity has been calculated according to the equation represented below:

r_ {1 (2)} = \ Delta [1 / T_ {1 (2)}] / [LGd]

where, r_ {1 (2)} is the longitudinal (transversal) relaxivity, Δ [1 / T_ {1 (2)}] is the difference between the inverse of the Longitudinal (transverse) relaxation times of the corresponding complex of Gd (III) and ligand and, [LGd] is the concentration of the complex of Gd (III) used (equal to the concentration of ligand).

NMR studies have been performed using aqueous solutions of Gd (III) -16 obtaining a relaxing value r_ {1} 2.04 and r_ {2} 2.58 s <-1> mM <-1> at 37 ° C, pH ~ 7.2 (25 ° C, pH ~ 7.2).

Claims (15)

1. The compounds of general formula I twenty-one his racemic mix, each of his enantiomers, their diastereomers or their pharmaceutically salts acceptable, in where R1 is selected from H or the radicals linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl, where each of these radicals is optionally substituted by one or more substituents, identical or different, independently chosen from halogen, hydroxy (-OH), oxo (-O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONR2), amine (-NH2), mono (-NHR) or disubstituted amine (-NRR '), mono (-CONHR) or disubstituted (-CONRR') carboxyamide, urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONRR '), aminocarbonoyl (-NRCOOR'), aryl, bicycles, heterocyclic nitrogen, oxygenated or saturated or unsaturated sulphide saturated containing 5 or 6 members; R 2 and R 4 are selected independently between H or linear alkyl radicals or branched, linear or branched alkenyl, where each of these radicals is optionally substituted by one or more substituents, identical or different, independently chosen between halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono amine (-NHR) or disubstituted (-NRR '), mono carboxyamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR or -NHCONRR '), or trisubstituted (-NRCONR'R' '), aminocarbonoyl (-NRCOOR '), aryl, bicyclo, nitrogen heterogenated, oxygenated or saturated or unsaturated sulphide containing 5 or 6 members; R 3 is selected from H or the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more identical or different substituents, independently chosen from halogen , hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN) , nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR' amine) ), monocarbonamide mono (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR' or -NHCONRR '), or trisubstituted (-NRCONR'R''), aminocarbonoyl (-NRCOOR') , mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), any of said cyclic radicals possibly being modified by one or more substituents, identical or different, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate
(-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenated, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members ; R 6, is selected from H or the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more identical or different substituents, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN ), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted amine (-NRR '), monocarbonamide mono (CONHR) or disubstituted (-CONRR'), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR ' ), mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), any of said cyclic radicals possibly being modified by one or more substituents, identical or different, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate
(-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenated, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members ; R 5 is one of the polyethylene derivatives cyclic or acyclic of general formula (II) or (III) 22 wherein Z is selected from H, Li, Na, K, N- methylglucosamine, benzyl or tert-butyl ( t- Bu); X represents a group selected from amides (-CONH- or -NHCO-), amines (-NR-), esters (-COO- or -OCO-),
ethers (-O-), thioethers (-S-), disulfides (-SS-), ureas (-NHCONH-), carbamates (-NHCOO- or -OCONH-), mono- or bicyclic aryls or heteroaryls nitrogen, oxygenated or sulphurated , saturated or unsaturated containing 5 or 6 members, or connectors of general formula IV 2. 3 where Ar represents a group mono or bicyclic aryl, or nitrogenous, oxygenated heteroaryl or sulphides containing 5 or 6 members; m, n, p and q are whole numbers selected from independently between 0, 1, 2, 3, 4 or 5; A, B, D, are each independently selected from the atoms of nitrogen (N), sulfur (S), oxygen (O) or carbon (C); if said atoms are N or C, they are optionally substituted by one or more substituents, identical or different, independently chosen from hydrogen, halogen, hydroxy (-OH), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR) 'or -NHCONR R''), or trisubstituted (-NRCONR'R''), aminocarbonoyl (-NRCOOR'), aryl, bicyclo, nitrogen heterogenated, oxygenated or sulphured, saturated or unsaturated containing 5 or 6 members, radicals linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl, any of said radicals possibly being substituted by one or more substituents, identical or different, chosen from the halogens s (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate
(-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenous, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members; R 7, is independently selected between H or linear or branched alkyl alkenyl radicals linear or branched, any of said radicals may be optionally substituted by one or more substituents, identical or different, chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR '), carboxyamide amine mono (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR or -NHCONRR '), or trisubstituted (-NRCONR'R' '), aminocarbonoyl (-NRCOOR '), aryl, bicyclo, heterocyclic nitrogen, oxygenated or saturated or unsaturated sulphide that It contains 5 or 6 members. R, R 'and R' 'can be selected so independent between hydrogen or linear alkyl radicals or branched, linear or branched alkenyl, linear alkynyl or branched, cycloalkyl, cycloalkenyl, bicycloalkyl, mono or bicycloaryl, saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S); being able be any of said radicals eventually substituted by one or more substituents, identical or different, chosen from halogen, hydroxy, acyloxy, cycloalkyl, cycloalkenyl, phenyl, cyano, nitro, carboxy or alkoxycarbonyl, nitrogen heterocycle, oxygenated or saturated or unsaturated sulfur containing 5 or 6 members. 2. A compound according to claim 1, in where, R 1, R 2, R 4, and R 7 are independently select between H or a linear alkyl radical or branched, R 3 and R 6 are selected from H or the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more identical or identical substituents. different, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl , cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono amine (-NHR) or disubstituted (-NRR '), monocarboxamide mono (CONHR) or disubstituted (-CONRR'), mono urea (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), any of said cyclic radicals possibly being modified by one or several substitutes. identical or different listeners, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR) , acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate
(-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenated, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members ; R 5 is selected from the structures of general formula (II) or (III)

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24

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wherein Z is selected from H, Li, Na, K, N- methylglucosamine, benzyl or tert-butyl ( t- Bu);

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X is selected from amide (-CONH- or -NHCO-), ester (-COO- or -OCO-), ether (-O-), thioethers (-S-), disulfides (-SS-), or connectors of general formula IV

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25

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where Ar represents a group mono or bicyclic aryl, or nitrogenous, oxygenated heteroaryl or sulphides containing 5 or 6 members; m, n, p and q are whole numbers selected from independently between 0, 1, 2, 3, 4 or 5; A, B and D are alkyl substituents. 3. A compound according to claim 2 in where A, B and D are -CH 2 -, X is an amide (-CONH-), m is 0, n and p are 2, q is 1, R 1, R 3 and R 6 are Me, R 2 and R 4 are H, R 5 is structure II, where Z is tert-butyl. 4. A compound according to claim 2 in where A, B and D are -CH 2 -, X is an amide (-CONH-), m is 0, n and p are 2, q is 1, R 2, R 3 and R 6 are Me, R 1 and R 4 are H, R 5 is structure II, where Z is tert-butyl. 5. A compound according to claim 2, in where A, B and D are -CH 2 -, X is an amide (-CONH-), m is 0, n and p are 2, q is 2, R2, R3, and R6 are Me, R1 and R 4 are H, R 5 is structure II, where Z is tert-butyl. 6. A compound of general formula VI

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26

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his racemic mix, each of his enantiomers, their diastereomers or their pharmaceutically salts acceptable, in where R1 is selected from H or the radicals linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl, where each of these radicals is optionally substituted by one or more substituents, identical or different, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONR2), amine (-NH2), mono (-NHR) or disubstituted amine (-NRR '), mono (-CONHR) or disubstituted (-CONRR') carboxyamide, urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONRR '), aminocarbonoyl (-NRCOOR'), aryl, bicycles, heterocyclic nitrogen, oxygenated or saturated or unsaturated sulphide saturated containing 5 or 6 members; R 2 and R 4 selects between H or the linear or branched alkyl, linear or branched alkenyl radicals, where each of these radicals is optionally substituted by one or more identical or different substituents, independently chosen from halogen , hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN) , nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate
(-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR or -NHCONRR '), or trisubstituted (-NRCONR'R''), aminocarbonoyl (-NRCOOR'), aryl, bicyclo, nitrogen heterogenated, oxygenated or saturated or unsaturated sulfur containing 5 or 6 members; R 3 is selected from H or the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more identical or different substituents, independently chosen from halogen , hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN) , nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR' amine) ), monocarbonamide mono (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR' or -NHCONRR '), or trisubstituted (-NRCONR'R''), aminocarbonoyl (-NRCOOR') , mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), any of said cyclic radicals possibly being modified by one or more substituents, identical or different, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate
(-OCOOR), carbamate (-OCONRR), amine (-NH2), mono (-NHR) or disubstituted (-NRR '), monocarbonamide (CONHR) or disubstituted (-CONRR'), urea mono ( -NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenated, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members; R 6, is selected from H or the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more identical or different substituents, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate
(-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2) alkoxycarbonyl
(-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted amine
(-NRR '), monocarbonamide mono (CONHR) or disubstituted (-CONRR'), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl ( -NRCOOR '), mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), any of said cyclic radicals possibly being modified by one or more substituents, identical or different, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (- COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (- NH 2), mono (-NHR) or disubstituted (-NRR '), monocarboxamide (CONHR), or disubstituted (-CONRR'), mono urea (-NHCONHR), di (-NRCONHR 'or -NHCONRR') ), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogen heterogenated, oxygenated or sulfurized saturated or unsaturated containing 5 or 6 members; R 8 one of the polyethylene derivatives cyclic or acyclic of general formula (VII) or

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27

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in which Z is selected from H, Li, Na, K, N- methylglucosamine; and Ln 3+ is selected from Gd, Eu, Tb, Dy, Ho, Er, Tm and Yb, X represents a group selected from amides (-CONH- or -NHCO-), amines (-NR-), esters (-COO- or -OCO-),
ethers (-O-), thioethers (-S-), disulfides (-SS-), ureas (-NHCONH-), carbamates (-NHCOO- or -OCONH-), mono- or bicyclic aryls or heteroaryls nitrogen, oxygenated or sulphurated , saturated or unsaturated containing 5 or 6 members, or connectors of general formula IV 28 where Ar represents a group mono or bicyclic aryl, or nitrogenous, oxygenated heteroaryl or sulphides containing 5 or 6 members; m, n, p and q are whole numbers selected from independently between 0, 1, 2, 3, 4 or 5; A, B, D, are each independently selected from the atoms of nitrogen (N), sulfur (S), oxygen (O) or carbon (C); if said atoms are N or C, they are optionally substituted by one or more substituents, identical or different, independently chosen from hydrogen, halogen, hydroxy (-OH), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR) 'or -NHCONRR''), or trisubstituted (-NRCONR'R''), aminocarbonoyl (-NRCOOR'), aryl, bicyclo, nitrogen heterogenated, oxygenated or sulphured, saturated or unsaturated containing 5 or 6 members, alkyl radicals linear or branched, linear or branched alkenyl, linear or branched alkynyl, any of said radicals possibly being substituted by one or more substituents, identical or different, chosen from the halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkyl, cycloalkenyl , phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate
(-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenous, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members; R 7 independently selected from H or the linear or branched alkyl, linear or branched alkenyl radicals, any of said radicals being optionally substituted by one or more substituents, identical or different, chosen from halogen, hydroxy (-OH ), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy
(-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl, cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate
(-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR or -NHCONRR '), or trisubstituted (-NRCONR'R''), aminocarbonoyl (-NRCOOR'), aryl, bicyclo, nitrogen heterogenated, oxygenated or saturated or unsaturated sulfur containing 5 or 6 members. R, R 'and R' 'can be selected so independent between hydrogen or linear alkyl radicals or branched, linear or branched alkenyl, linear alkynyl or branched, cycloalkyl, cycloalkenyl, bicycloalkyl, mono or bicycloaryl, saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S); being able be any of said radicals eventually substituted by one or more substituents, identical or different, chosen from halogen, hydroxy, acyloxy, cycloalkyl, cycloalkenyl, phenyl, cyano, nitro, carboxy or alkoxycarbonyl, nitrogen heterocycle, oxygenated or saturated or unsaturated sulfur containing 5 or 6 members. 7. A compound according to claim 6, in where, R1, R2, R4 and R7 are independently select between H or a linear alkyl radical or branched, R 3 and R 6 are selected from H or the linear or branched alkyl, linear or branched alkenyl, linear or branched alkynyl radicals, where each of these radicals is optionally substituted by one or more identical or identical substituents. different, independently chosen from halogen, hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR), acyl (-COR), cycloalkenyl , cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate (-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono amine (-NHR) or disubstituted (-NRR '), monocarboxamide mono (CONHR) or disubstituted (-CONRR'), mono urea (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), mono or bicycloaryl, mono or bicyclo saturated or unsaturated heterocycles (having a maximum of 5 heteroatoms selected from N, O and S), any of said cyclic radicals possibly being modified by one or several substitutes. identical or different listeners, chosen from halogens (-X), hydroxy (-OH), oxo (= O), thiol (-SH), thiolate (-SR), alkoxy (-OR), acyloxy (-OCOR) , acyl (-COR), cycloalkyl, cycloalkenyl, phenyl (-Ph), cyano (-CN), nitro (-NO2), alkoxycarbonyl (-COOR), carbonate
(-OCOOR), carbamate (-OCONRR '), amine (-NH2), mono (-NHR) or disubstituted (-NRR'), monocarbonamide (CONHR) or disubstituted (-CONRR '), urea mono (-NHCONHR), di (-NRCONHR 'or -NHCONRR'), or trisubstituted (-NRCONR'R ''), aminocarbonoyl (-NRCOOR '), nitrogenated, oxygenated or saturated or unsaturated heterocyclic containing 5 or 6 members ; R 8 is selected from the structures of general formula (VII) or (VIII) 29 wherein Z is selected from H, Li, Na, K, N- methylglucosamine; X is selected from amide (-CONH- or -NHCO-), ester (-COO- or -OCO-), ether (-O-), thioethers (-S-), disulfides (-SS-), or connectors of general formula IV

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30

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where Ar represents a group mono or bicyclic aryl, or nitrogenous, oxygenated heteroaryl or sulphides containing 5 or 6 members; m, n, p and q are whole numbers selected from independently between 0, 1, 2, 3, 4 or 5; A, B and D are alkyl substituents. Ln + 3 is Gd, Eu, Tb, Dy, Ho, Er, Tm and Yb. 8. A compound according to claim 7 in where A, B and D are -CH 2 -, X is an amide (-CONH-), m is 0, n and p are 2, q is 1, R 1, R 3 and R 6 are Me, R 2 and R 4 are H, R 8 is structure II, where Z can be H, Li, Na, K, or N-methylglucosamine and the lanthanide Ln3 + is selected from Gd, Eu, Tb, Dy, Ho, Er, Tm and Yb. 9. A compound according to claim 7 in where A, B and D are -CH 2 -, X is an amide (-CONH-), m is 0, n and p are 2, q is 1, R 2, R 3 and R 6 are Me, R 1 and R 4 are H, R 8 is structure II, where Z can be H, Li, Na, K, or N-methylglucosamine and the lanthanide Ln3 + is selected from Gd, Eu, Tb, Dy, Ho, Er, Tm and Yb. 10. A compound according to claim 7 in where A, B and D are -CH 2 -, X is an amide (-CONH-), m is 0, n and p are 2, q is 2, R2, R3 and R6 are Me, R1 and R 4 are H, R 8 is structure II, where Z can be H, Li, Na, K, or N-methylglucosamine and the lanthanide Ln3 + is selected from Gd, Eu, Tb, Dy, Ho, Er, Tm and Yb. 11. A procedure for obtaining compounds of formula VI, according to claim 6, comprising the reaction of a compound of general formula I, according to the claim 1, and a lanthanide chloride in water. 12. A method according to claim 11, wherein the compounds of general formula I are obtained by the coupling between the compound of formula (IX) and the ligand type (II) or ligand type (III), 31 where Y is selected from carboxylic acid, amine, alcohol, thiol, azide, terminal alkene, terminal haluroalkene, terminal alkyne, monocyclic aryl halide or bicyclic, saturated cyclic mono or bicyclic haloheterocycle or unsaturated; Y 'represents a group selected from acids carboxylic, amines, alcohols, thiols, azides, alkenes terminals, haluroalkenes terminals, alkynes terminals, halides monocyclic or bicyclic aryl, monocyclic haloheterocycles or saturated or unsaturated bicyclics; And and Y 'are chosen so that its reactivities allow to form a covalent bond between they. 13. The use of the compounds of formula VI in the manufacture of contrast agents for Resonance Imaging Magnetic (IMR) in clinical diagnosis. 14. A pharmaceutical composition comprising a compound according to claim 6 and at least one excipient or pharmaceutically acceptable vehicle. 15. A method for diagnosing IMR atherosclerosis in a mammal, which comprises administer to a mammal that needs an effective amount of a compound according to claim 6.