Patent FR-2856689-A1 (FR)
Title: New targeted diagnostic agents, used especially for detecting cardiovascular, cancerous or inflammatory disorders, comprise high relaxivity signal moiety bonded via linker to biovector
Inventor: PORT MARC
IPC: A61P35/00
Filed: 2003-06-25
Abstract: New targeted diagnostic agents (I) comprise a high relaxivity signal moiety (e.g. a gadolinium-cyclic polyamine complex) bonded via a linker to a biovector, specifically in a dendrimer structure. Targeted diagnostic agent compounds of formula B'x-Lz-(Ch)y (I) and their addition salts with mineral or organic acids or bases are new. B' : biovector; L : linker; Ch : chelate of formula (D)q-(R)r; R : gadolinium-cyclic polyamine complex of formula (a) or (b) or a polyamine residue of formula XCHR1N(Q7)CH2CH2N(Q8)N(CHR1X)2; Q1Rh and Q2 = U; or Q1U' and Q2 = CHR1X; one of Q3 and Q4CHR1X and the other = U, Q5 = Rg and Q6 = Rh; or Q3, Q4CHR1X, Q5 = Rg and Q6 = U'; or Q3, Q4CHR1X, Q5 = U' and Q6 = Rh; one of Q7 and Q8U and the other = CHR1X; X : C(O)ORa', C(O)NRb'Rc' or P(Rd')O2H; Ra'-Rc'H or 1-8C alkyl; Rd'OH, 1-8C alkyl, 1-8C alkoxy, aryl(1-8C) alkyl or 1-8C alkoxyalkyl; R1hydrophilic group of molecular weight > 200, selected from (2-3C) polyoxyalkylene (specifically polyethylene glycol or its 1-3C monoether or monoester) of molecular weight 1000-2000, polyhydroxyalkyl, polyol or (R2G)e((R2G)iR3)h; h : 1 or 2; i : 0-2; e : 1-5; R2bond, alkylene, alkoxyalkylene or polyalkoxyalkylene or phenylene or optionally unsaturated heterocycle (both optionally substituted by OH, Cl, Br, I, 1-8C alkyl, 1-8C alkoxy, NO2, NRxRy, NRxC(O)Ry, C(O)NRxRy, C(O)ORx or T); Rx, RyH or 1-8C alkyl; T : 1-14C alkyl, cycloalkyl, alkylene or alkoxy; G : bond, O, C(O), OC(O), C(O)O, OSO2, C(O)NR', NR'C(O), NR'C(O)O, OC(O)NR', NR', NR'C(S), C(S)NR', SO2NR', NR'SO2, NR'C(S)O, OC(S)NR', NR'C(S)NR', P(O)(OH)NR' or NR'P(O)(OH); R' : H, 1-8C alkyl or R3; R3alkyl (optionally interrupted or substituted by phenyl), alkyleneoxy, phenyl or amino or amido (both optionally substituted by alkyl (optionally interrupted or substituted by phenyl), phenylene or heterocyclyl (both optionally substituted by OH, Cl, Br, I, 1-8C alkyl, 1-8C alkoxy, NO2, NRxRy, NRxC(O)Ry, C(O)NRxRy or T); Ra-RiH, alkyl, hydroxyalkyl, alkylphenyl or cycloalkyl; U : CXR4L1, CXR4C(O)NL1 or CXR4CHR5OHL1; R4, R5H, alkyl or hydroxyalkyl; L1, U' : linker ensuring a linkage between Ch and L if q = 0 or between Ch and D if q = 1; q : 0 or 1; r : 1 when q = 0; or r : 2-5 when q = 1; D : polyfunctional residue capable of bonding L to at least two Ch; x, y, z : 1-8, provided that y = z. [Image] Independent claims are also included for: (a) new intermediates of formula L-((D)q-(R)r (II); (b) metal-bonded forms of (I), having formula Bx-Lz-(Ch)y-M (I'); and (c) a method of preparation of (I). M : ion of a paramagnetic metal of atomic number 21-29, 42-44 or 58-70; a radionuclide such as technetium-99. tin-117, indium-111, ruthenium-97, gallium-67 or -68, zirconium-89, lutetium-177, scandium-47, rhodium-105, rhenium-188, copper-60, -64 or -67, yttrium-90, gadolinium-159, promethium-149 or holmium-166 or a heavy metal of atomic number 21-31, 39-49, 50, 56-80. 82, 83 or 90.