RU2008120336A - MULTI-DIMENSIONAL CONTRAST AGENTS FOR MAGNETIC RESONANCE - Google Patents

Abstract

1. The compound of formula (II), consisting of a core and groups -R-L-X 'attached to the specified core,! ! where A represents a carbon atom or an aromatic ring; ! R are the same or different, and R means a group that is an obstacle to the rotation of the covalent bond between the core of A and R and / or the covalent bond between R and L and / or L and X, if L is present, and / or the covalent bond between R and X 'if L is absent; ! L are present or absent, and, if present, are the same or different, and L means a linker group; ! X 'are the same or different, and X' means a paramagnetic chelate consisting of a chelator X and a paramagnetic metal ion M; and! n is an integer of 3 or 4.! 2. The compound according to claim 1, where A is an aromatic ring containing at least 3 carbon atoms and possibly one or more than one N, S or O heteroatom, said ring being optionally substituted with one or more of one of the following substituents: C 1 -C 3 alkyl, possibly substituted with hydroxyl or amino groups, amino or hydroxyl groups or halogen, provided that n attachment points are left for RLX groups. ! 3. The compound according to claim 1, where R is a slowly rotating group with a conformation lifetime of more than 0.1 μs. ! 4. The compound according to claim 1, where R is a group whose rotation is hindered by steric interaction with the core A and / or L, if L is present, and / or X, and / or other groups R.! 5. The compound according to claim 1, where L is present. ! 6. The compound according to claim 1, where X is selected from the residues of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DTPA (diethylenetriaminopentaacetic acid), BOPTA (4-carboxy-5 , 8.1

Claims (18)

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

where A represents a carbon atom or an aromatic ring; R are the same or different, and R means a group that is an obstacle to the rotation of the covalent bond between the core of A and R and / or the covalent bond between R and L and / or L and X, if L is present, and / or the covalent bond between R and X 'if L is absent; L are present or absent, and, if present, are the same or different, and L means a linker group; X 'are the same or different, and X' means a paramagnetic chelate consisting of a chelator X and a paramagnetic metal ion M; and n is an integer of 3 or 4. 2. The compound according to claim 1, where A is an aromatic ring containing at least 3 carbon atoms and possibly one or more than one N, S or O heteroatom, said ring being optionally substituted with one or more of one of the following substituents: C ₁ -C ₃ alkyl, possibly substituted with hydroxyl or amino groups, amino or hydroxyl groups or halogen, provided that n attachment points are left for RLX groups. 3. The compound according to claim 1, where R is a slowly rotating group with a conformation lifetime of more than 0.1 μs. 4. The compound according to claim 1, where R is a group whose rotation is hindered by steric interaction with the core A and / or L, if L is present, and / or X, and / or other groups R. 5. The compound according to claim 1, where L is present. 6. The compound according to claim 1, where X is selected from the residues of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DTPA (diethylenetriaminopentaacetic acid), BOPTA (4-carboxy-5 , 8,11-tris (carboxymethyl) -1-phenyl-2-oxa-5,8,11-triazatridecan-13-oic acid), DO3A (1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid), HPDO3A (10- (2-hydroxypropyl) -1,4,7,10-tetraazacyclodecane-1,4,7-triacetic acid), MCTA (2-methyl-1,4,7,10-tetraazacyclodecane - 1,4,7,10-tetraacetic acid), DOTMA (tetramethyl-1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid), DMA BMA (N, N-bis [2- [ carboxymethyl [(methylcarba oyl) methyl] amino] ethyl] glycine), M4DOTA ([(2S, 5S, 8S, 11S) -4,7,10-tris-carboxymethyl-2,5,8,11-tetramethyl-1,4, 7,10-tetraazacyclododecan-1-yl] acetic acid), M4DO3A ([(2S, 5S, 8S, 11S) -4,7-bis-carboxymethyl-2,5,8,11-tetramethyl-1,4,7 , 10-tetraazacyclo-dodecan-1-yl] -acetic acid), PCTA (3,6,9,15-tetraazabicyclo [9.3.1] pentadeca-1 (15), 11,13-triene-3,6,9- triacetic acid), TETA (N, N'bis (2-aminoethyl) -1,2-ethanediamine), TRITA (1,4,7,10-tetraazacyclotridecan-N, N ', N' ', N' '' - tetraacetic acid), NETA (1,12-dicarbonyl, 15- (4-isothiocyanatobenzyl) -1,4,7,10,13-pentaazacyclohexadecane-N, N ', N' '- triacetic acid), DPDP, EDTA (ethylene diamine tetra susne acid) or EDTP. 7. The compound according to claim 1, where M is a paramagnetic ion of a transition metal or lanthanide metal. 8. The compound according to any one of claims 1 to 7, where all R are the same, and / or all L, if present, are the same, and / or all X 'are the same. 9. A composition comprising a compound according to any one of claims 1 to 8 and at least one physiologically acceptable carrier. 10. The composition according to claim 9 for use as an agent in MR (magnetic resonance) imaging or as an agent in MR spectroscopy. 11. The use of the composition according to claim 9 as a contrast agent in MR imaging or as an agent in MR spectroscopy. 12. The method of MR imaging and / or MR spectroscopy, in which the composition according to claim 9 is administered to the subject, and the subject is subjected to an MR procedure in which MR signals emanating from the subject or parts of the subject in which the composition is distributed, and in accordance with the detected signals, it is possible to generate MR tomograms and / or MR spectra. 13. The method of MR imaging and / or MR spectroscopy, in which the subject to whom the composition according to claim 9 was previously introduced is subjected to an MR procedure in which MR signals originating from the subject or parts of the subject in which the composition is distributed are detected. , and in accordance with the detected signals, it is possible to generate MR tomograms and / or MR spectra. 14. The compounds of formula (I), consisting of a core and groups -R-L-X attached to the specified core,

where A represents a carbon atom or an aromatic ring; R are present or absent, and if present, are the same or different, and R means a moiety that is an obstacle to the rotation of the covalent bond between the core A and R and / or the covalent bond between R and L and / or L and X, if L is present, and / or a covalent bond between R and X, if L is absent; L are present or absent, and, if present, are the same or different, and L means a linker group; X are the same or different, and X means a chelator; and n is an integer of 3 or 4. 15. The method of producing compounds according to 14, including a) the use as the first building block of core A, which is substituted by reactive groups involving the addition of R; b) the interaction of R or its predecessor with the specified first building block with the formation of the second building block, consisting of a core A and R; c) possibly the interaction of L or its predecessor with the specified second building block with the formation of the third building block, consisting of the core A, R and L; and d) the interaction of X or its predecessor with the specified second or third building block. 16. The method of producing compounds according to 14, including a) the use of the first building block, consisting of a core A and R, condensed with A or attached to A, where R is substituted by reactive groups involving the addition of L or X; b) it is possible the interaction of L or its predecessor with said first building block to form a second building block consisting of a core A, R and L, and c) the interaction of X or its predecessor with the specified first or second building block. 17. The method of producing compounds according to 14, including a) trimerization or tetramerization of a monomer containing a group which, after trimerization or tetramerization, forms A, wherein said monomer further comprises R containing a reactive group or its precursor, comprising attaching L or its precursor, if L is present, or X or its precursor, c the formation of an intermediate compound; b) possibly the interaction of L or its predecessor with the specified intermediate compound; and c) the interaction of X or its precursor with the intermediate compound or reaction product of stage b). 18. The method of producing compounds according to any one of claims 1 to 8, comprising the implementation of any of the methods according to claims 15-17 and the subsequent stage, including the complexation of the reaction product of any of these methods according to claims 15-17 with a suitable paramagnetic metal ion M .