Claims for Patent: 8,114,863

Summary for Patent: 8,114,863

Title:	Compounds comprising short aminoalcohol chains and metal complexes for medical imaging
Abstract:	The present invention relates to a compound of formula (II) chosen from (IIa) and (IIb) or of formula (VI) chosen from (VIa) and (VIb) of following general formulae: in which: X1, X2, X3, X4 and X5 represent, independently of one another, L-Y in which L represents a C1-C3 alkyl group, preferably (CH2)n with n=1 to 3, Y represents —CONH2, —CO—NR7R8 or —NR8-CO—R8, or an isomer, an enantiomer or a diastereoisomer of these or their mixtures or a pharmaceutically acceptable salt of the compounds of formulae (VIa) and (VIb). It also relates to a complex of these compounds with a paramagnetic metal or a radionuclide and their use in diagnostic methods.
Inventor(s):	Marc Port
Assignee:	Guerbet SA
Application Number:	US12/083,092
Patent Claims:	1. A compound having formula (IIa): in which: R1, R2 and R3 represent, independently of one another, —COOH, —P(O)(OH)2 or —R6—P(O)—OH in which R6 represents an H atom or a C1-C3 alkyl group; X1, X2 and X3 represent, independently of one another, L-Y in which L represents a C1-C3 alkyl group, Y represents —CONH2, —CO—NR7R8 or —NR7-CO—R8, in which R7 represents H, a C1-C6 alkyl group or a C1-C6 hydroxyalkyl group, and R8 represents a C1-C6 alkyl or C1-C6 hydroxyalkyl group, provided that at least R7 or R8 represents a C1-C6 hydroxyalkyl group; D represents CH or N; E represents CH or N; F1 represents CH or N; K1 to K12 each independently represent H, —(CH2)j—CH3 or —(CH2)i—OH, in which j=0 to 3 and i=1 to 3, or K3 or K4 with K5 or K6, and/or K7 or K8 with K9 or K10 form a ring having 3 to 6 carbon atoms; or an isomer, an enantiomer or a diastereoisomer of these or their mixtures. 2. Compound according to claim 1 of formula (IIa), wherein E represents an N atom and D and F1 represent CH. 3. Compound according to claim 1 of formula (IIa), wherein X1, X2 and X3 independently represent —(CH2)n—CO—NR7R8 or —(CH2)n—NR7-CO—R8, in which n is between 1 and 3, R7 represents H or a methyl group and R8 represents a C1-C6 hydroxyalkyl group. 4. Compound according to claim 3 of formulae (IIa) wherein X1, X2 and X3 independently represent —(CH2)n—CONR7R8 or —(CH2)n—NR7-CO—R8, in which n is between 1 and 3, R7 represents H or a methyl group and R8 represents a C1-C4 hydroxyalkyl group. 5. Compound according to claim 4, wherein X1, X2 and X3 independently represent —(CH2)n—CONR7R8, in which n is between 1 and 3, R7 represents H and R8 represents —CH2—CH2OH, —CHOH—CH2OH, —CH—(CH2OH)2, —CH2—(CHOH)p—CH2OH, with p=1 to 4, or —C—(CH2OH)3. 6. Multimer of a compound according to claim 1. 7. Complex of a compound according to claim 1 with M, M representing an ion of a paramagnetic metal of atomic number 21-29, 42-44 or 58-70 or a radionuclide chosen from 99Tc, 117Sn, 111In, 97Ru, 67Ga, 68Ga, 89Zr, 177Lu, 47Sc, 105Rh, 188Re, 60Cu, 62Cu, 64Cu, 67Cu, 90Y, 159Gd, 149Pr and 166Ho. 8. Complex of a multimer according to claim 6 with M, M representing an ion of a paramagnetic metal of atomic number 21-29, 42-44 or 58-70 or a radionuclide chosen from 99Tc, 117Sn, 111In, 97Ru, 67Ga, 68Ga, 89Zr, 177Lu, 47Sc, 105Rh, 188Re, 60Cu, 62Cu, 64Cu, 67Cu, 90Y, 159Gd, 149Pr and 166Ho. 9. Complex according to claim 7 or 8, wherein the ion of a paramagnetic metal is chosen from Gd3+, Mn2+ and Fe3+. 10. Complex according to claim 7 or 8, wherein it exhibits: a relaxivity in water of at least 10 mM−1s−1Gd−1, an osmolality of between 800 and 1200 mOsm/kg, for a Gd concentration of 400 to 600 mM, and a substantially stable relaxivity between 20 and 300 MHz, or an increase in relaxivity beyond 20 MHz. 11. Complex according to claim 7 or 8, wherein it is chosen from the complexes of following formulae: 12. Complex according to claim 7 or 8, wherein it is chosen from the complexes of following formulae: 13. Pharmaceutical composition comprising a compound according to claim 1 or a multimer according to claim 6 or a complex according to claim 7 or 8, a pharmaceutically acceptable vehicle and optionally formulation additives. 14. Lipid pharmaceutical composition comprising a compound according claim 1 or a multimer according to claim 6 or a complex according to claim 7 or 8, bonded to a lipid nanoparticle. 15. Diagnostic composition for magnetic resonance imaging, comprising a compound according to claim 1 or a multimer according to claim 6 compound according to claim 9 or a complex according to claim 7 or 8. 16. Process for the preparation of a metal complex according to claim 7 of a compound of formula (IIa) in which X1, X2 and X3 independently represent —(CH2)n—CO—NR7R8, in which n=1 to 3 and R7 and R8 are as defined in claim 1, comprising the stages: a) reacting the condensed macrocycle of following formula (IV) in which D, E and F1 are as defined in claim 1, with a compound of formula R′OOC—CHQ-(CH2)n—COOR′, in which n=1 to 3, Q represents a leaving group, and R′ represents H or a (C1-C3)alkyl or benzyl group, in order to obtain the hexaacid or ester of following formula (V) b) optionally hydrolysing or hydrogenating the ester functional groups of the hexaacid of formula (V) when R′ is other than H, in order to obtain the hexaacid of formula (Va) in which D, E and F1 are as defined above and n is between 1 and 3; c) reacting the hexaacid of formula (Va) with a salt or an oxide of the metal to be complexed, in order to obtain the corresponding complex or one of its salts with a base; d) reacting the complex, in the presence of an agent which activates carboxylic acid functional groups, with the aminoalcohol group or groups NHR7R8, in which R7 and R8 are as defined in claim 1, in order to obtain the triamide of formula (IIa), in which X1, X2 and X3 independently represent —(CH2)n—CO—NR7R8 in which n=1 to 3 and R7 and R8 are as defined in claim 1.