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BR-122022003776-B1 - Isomeric mixtures comprising PCTA-based contrast agents, their uses and preparation processes.

BR122022003776B1BR 122022003776 B1BR122022003776 B1BR 122022003776B1BR-122022003776-B1

Abstract

The present invention relates to the RRR/SSS enantiomer pair of Gd (PCTA - tris-glutamic acid), to the individual enantiomers of the pair, to pharmaceutically acceptable salts thereof, their amide derivatives and compositions comprising at least 50% of these compounds.

Inventors

  • Roberta Napolitano
  • Luciano Lattuada
  • Zsolt BARANYAI
  • Nicole GUIDOLIN
  • Giuseppe Marazzi

Assignees

  • BRACCO IMAGING SPA

Dates

Publication Date
20260310
Application Date
20190806
Priority Date
20180806

Claims (11)

  1. 1. Isomeric mixture of the Gd(PCTA - tris-glutaric acid) complex with the formula: characterized by the fact that at least 50% of the complex consists of the enantiomer [(αR,α'R,α''R)-α,α',α''-tris(2-carboxyethyl)-3,6,9,15-tetra-azabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetato(3-)-KN3,KN6,KN9,KN15,KO3,KO6,KO9]-gadolinium (RRR enantiomer): the enantiomer [(αS,α'S,α''S)-α,α',α''-tris(2-carboxyethyl)-3,6,9,15-tetra-azabicyclo[9.3.1]pentadeca-1 (15),11,13-triene-3,6,9-triacetate(3-)-KN3,KN6,KN9,KN15,KO3,KO6,KO9]-gadolinium which (SSS enantiomer): or a mixture of its RRR and SSS enantiomers.
  2. 2. Isomeric mixture according to claim 1, characterized in that at least 60% of the complex consists of the RRR enantiomer of formula (Ia), the SSS enantiomer of formula (Ib), or a mixture thereof.
  3. 3. Isomeric mixture, according to claim 1 or 2, characterized in that at least 80% of the complex consists of the RRR enantiomer of formula (Ia), the SSS enantiomer of formula (Ib), or a mixture thereof.
  4. 4. Isomeric mixture, according to any one of claims 1 to 3, characterized in that at least 90% of the complex consists of the RRR enantiomer of formula (Ia), the SSS enantiomer of formula (Ib), or a mixture thereof.
  5. 5. Process for the preparation of [(αR,α'R,α''R)-α,α',α''-tris(2-carboxyethyl)-3,6,9,15-tetra-azabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetato(3-)-KN3,KN6,KN9,KN15,KO3,KO6,KO9]-gadolinium, as defined in claim 1, characterized in that it comprises: a) obtaining a dimethyl ester of (2S)-2-[(trifluoromethylsulfonyl)oxy]pentanedioic acid of formula b) alkylation of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene of formula with the dimethyl ester of (2S)-2-[(trifluoromethylsulfonyl)oxy]pentanedioic acid collected from step a) to obtain the compound of formula X (c) convert the compound with formula X into the corresponding gadolinium complex.
  6. 6. Process for the preparation of [(αS,α'S,α''S)-α,α',α''-tris(2-carboxyethyl)-3,6,9,15-tetra-azabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetato(3-)-KN3,KN6,KN9,KN15,KO3,KO6,KO9]-gadolinium, as defined in claim 1, characterized in that it comprises: a') obtaining a dimethyl ester of (2R)-2-[(trifluoromethylsulfonyl)oxy]pentanedioic acid of formula b') alkylation of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene of formula with the dimethyl ester of (2R)-2-[(trifluoromethylsulfonyl)oxy]pentanedioic acid collected from step a') to obtain the compound of formula XV c') convert the compound with formula XV into the corresponding gadolinium complex.
  7. 7. Process for the preparation of the isomeric mixture of formula (II B):F'(NR1R2)3 (II B) in which:F' is an isomeric mixture of a Gd(PCTA - tris-glutaric acid) residue of formula III, conjugated with amino residues of formula -NR1R2 through the open bonds of the carboxyl portions identified with a complete circle (•) in formula III above to provide the corresponding amide derivative of formula wherein: the said isomeric mixture of Gd residue (PCTA-tris-glutaric acid) comprises at least 50% of an RRR enantiomer residue of formula (IIIa): of an enantiomeric residue SSS of formula (IIIb) or a mixture of said enantiomeric residues; each of the three -NR1R2 groups is linked to an open bond of a respective carboxyl (•) moiety of F'; R1 is H; R2 is -CH2CH(OH)CH2OH; the process being characterized in that it comprises: a) obtaining an isomeric mixture of the Gd(PCTA-tris-glutaric acid) complex, as defined in claim 1, comprising at least 50% of the RRR or SSS enantiomer, or a mixture thereof; b) converting the isomeric mixture of Gd(PCTA-tris-glutaric acid) obtained from step a) into the corresponding isomeric mixture of the respective amide derivative, by reacting the product recovered from step a) with isoserinol.
  8. 8. Use of a pharmaceutical composition comprising an isomeric mixture, as defined in any one of claims 1 to 4, in mixture with one or more pharmaceutically acceptable excipients, characterized in that it is for use as a diagnostic composition.
  9. 9. Use of a pharmaceutical composition comprising an isomeric mixture of formula (II B):F'(NR1R2)3 (II B), prepared by the process as defined in claim 7, wherein:F' is an isomeric mixture of a Gd(PCTA - tris-glutaric acid) residue of formula III, conjugated with amino residues of formula -NR1R2 through the open bonds of the carboxyl portions identified with a complete circle (•) in formula III above to provide the corresponding amide derivative of formula wherein: the said isomeric mixture of Gd residue (PCTA-tris-glutaric acid) comprises at least 50% of an RRR enantiomer residue of formula (IIIa): of an enantiomeric residue SSS of formula (IIIb) or a mixture of said enantiomeric residues; each of the three -NR1R2 groups is linked to an open bond of a respective carboxyl moiety (•) of F'; R1 is H; R2 is -CH2CH(OH)CH2OH, in a mixture with one or more pharmaceutically acceptable excipients, characterized in that it is for use as a diagnostic composition.
  10. 10. Use of a pharmaceutically acceptable salt of an isomeric mixture, as defined in any one of claims 1 to 4, characterized in that it acts as a contrast agent for Magnetic Resonance Imaging (MRI).
  11. 11. Use of a pharmaceutically acceptable salt of an isomeric mixture of formula (II B):F'(NR1R2)3 (II B), prepared by the process as defined in claim 7, wherein:F' is an isomeric mixture of a Gd(PCTA - tris-glutaric acid) residue of formula III, conjugated with amino residues of formula -NR1R2 through the open bonds of the carboxyl portions identified with a complete circle (•) in formula III above to provide the corresponding amide derivative of formula wherein: the said isomeric mixture of Gd residue (PCTA-tris-glutaric acid) comprises at least 50% of an RRR enantiomer residue of formula (IIIa): of an enantiomeric residue SSS of formula (IIIb) or a mixture of said enantiomeric residues; each of the three -NR1R2 groups is linked to an open bond of a respective carboxyl portion (•) of F'; R1 is H; R2 is -CH2CH(OH)CH2OH, characterized by the fact that it is as a contrast agent for Magnetic Resonance Imaging (MRI).

Description

Field of Invention [0001] The present invention relates generally to the field of Magnetic Resonance Imaging (MRI). More particularly, it relates to PCTA-based contrast agent isomers and to MRI contrast agents enriched with these isomers. Background of the Invention [0002] Contrast agents for magnetic resonance imaging used in daily diagnostic practice typically include gadolinium complex compounds characterized by high stability constants that ensure protection against in vivo release of the free metal ion (which is known to be extremely toxic to living organisms). [0003] Another key parameter in defining the tolerability of a gadolinium-based contrast agent is the kinetic inertia (or kinetic stability) of the Gd(III) complex, which is estimated through the dissociation half-life (t1/2) (i.e., reversal of complex formation) of the complex. [0004] High inertness becomes crucial, particularly for those complex compounds with lower thermodynamic stability and/or longer retention time before excretion, in order to avoid or minimize possible reversal reactions of complex formation or transmetalation. [0005] Document EP1931673 (Guerbet) describes PCTA derivatives with the formula: and a synthetic route for its preparation. [0006] Document EP 2988756 (same Applicant) described a pharmaceutical composition comprising the above derivatives together with a calcium complex of 1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetraacetic acid. According to document EP 2988756, the calcium complex compensates for the weak thermodynamic stability observed for gadolinium complexes based on PCTA, forming, through transmetalation, a strong complex with a free lanthanide ion, thereby increasing the tolerability of the contrast agent. [0007] Both document EP1931673 and document EP2988756 also refer to enantiomers or diastereomers of the claimed compounds, or mixtures thereof, preferably chosen from the diastereomers RRS, RSR and RSS. [0008] Both patents above describe, among specific derivatives, (α3, α6, α9)-tris(3-((2,3-dihydroxypropyl)amino)-3-oxopropyl)-3,6,9,15-tetra-azabicyclo(9.3.1)pentadeca-1(15),11,13-triene-3,6,9-triacetate(3-)-(KN3,KN6,KN9,KN15,Kθ3,Kθ6,Kθ9)gadolinium, more recently identified as gadolinium chelate of 2,2',2"-(3,6,9-triaza-1(2,6)-pyridinecyclodecafano-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid) (number CAS registry number: 933983-75-6), which has the following formula: otherwise identified as P03277 or Gadopiclenol. [0009] For Gadopiclenol, document EP1931673 reports a relaxivity of 11 mM-1s-1Gd-1 (in water, at 0.5 T, 37 °C), while document EP 2988756 reports a thermodynamic equilibrium constant of 10-14.9 (log Kterm = 14.9). [0010] Furthermore, for this same compound, a relaxivity value of 12.8 mM-1s-1 in human serum (37 °C, 1.41 T), stability (log Kterm) of 18.7 and dissociation half-life of about 20 days (at a pH of 1.2; 37 °C) were reported by the proprietor (Investigative Radiology 2019, Vol. 54, (8), 475-484). [0011] The precursor for the preparation of the PCTA derivatives described in document EP1931673 (including Gadopiclenol) is the Gd complex of 3,6,9,15-tetra-azabicyclo-[9.3.1]pentadeca-1(15),11,13-triene-tri(α-glutaric) acid which has the following formula: identified in this document as "Gd(PCTA - tris-glutaric acid)". In particular, Gadopiclenol is obtained by amidation of the previous compound with isoserinol. [0012] As noted by the Applicant, Gd(PCTA - tris-glutaric acid) has three stereocenters in the glutaric moieties (identified with an asterisk (*) in the structure above) which lead to 2³ = 8 possible stereomers. More specifically, the structure above can generate four pairs of enantiomers, outlined in Table 1 below: Table 1 [0013] The RRR isomer is the mirror image of the SSS isomer, which is why they are called enantiomers (or enantiomer pairs). As is known, enantiomers exhibit the same physicochemical properties and are distinguishable only using chiral methodologies, such as chiral chromatography or polarized light. [0014] On the other hand, the RRR isomer is neither the same as nor a mirror image of any of the other six isomers above; these other isomers are thus identified as diastereomers of the RRR (or SSS) isomer. Diastereomers may exhibit different physicochemical properties (e.g., melting point, water solubility, relaxivity, etc.). [0015] Regarding Gadopiclenol, its chemical structure contains a total of six stereocenters, three in the glutaric portions of the precursor as discussed above and one in each of the three isoserinol portions linked to it, identified in the following structure with an asterisk (*) and a hollow circle (°), respectively: [0016] This leads to a total theoretical number of 26 = 64 stereomers for this compound. [0017] However, neither document EP1931673 nor document EP 2988756 describes the exact composition of the isomeric mixture obtained following the reported synthetic route, nor does either of them provide any instructio