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WO2008134289A2 - Complexes de lanthanide insaturés de manière coordonnée à relaxivité élevée - Google Patents

Complexes de lanthanide insaturés de manière coordonnée à relaxivité élevée Download PDF

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Publication number
WO2008134289A2
WO2008134289A2 PCT/US2008/061078 US2008061078W WO2008134289A2 WO 2008134289 A2 WO2008134289 A2 WO 2008134289A2 US 2008061078 W US2008061078 W US 2008061078W WO 2008134289 A2 WO2008134289 A2 WO 2008134289A2
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groups
macrocycle
ionizable
group
coordinating
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PCT/US2008/061078
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WO2008134289A3 (fr
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Dennis A. Moore
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Mallinckrodt Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
    • A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA

Definitions

  • the present invention generally relates to stable MRI contrast agents that exhibit enhanced relaxivity.
  • Diagnostic imaging is an important non-invasive tool for the evaluation of pathology and physiology.
  • CT computerized tomography
  • MRI nuclear magnetic resonance imaging
  • Proton MRI is based on the acquisition of images underlining the physical properties of hydrogen nuclei, or "protons", in different environments.
  • the most abundant proton source in biological tissues is water. It is the quantum mechanical "spin" of the water proton nuclei that ultimately gives rise to the signal in all imaging experiments.
  • the distinguishing feature of MRI agents is the presence of unpaired electrons within their atomic orbitals, which create local magnetic fields (paramagnetism) that interact with the nuclear spins of tissue water protons (hydrogen). In some instances, the atoms bearing unpaired electrons may be organized into groups (domains) that exert even greater local magnetic fields (superparamagnetism).
  • the sample to be imaged is placed in a strong homogeneous static magnetic field (on the order of 1-12 Tesla).
  • the presence of the magnetic field results in the redistribution of the proton spins into the two allowed quantum mechanical states, i.e., approximately one half aligned with the field (parallel; lower energy level) and the other half against the field (antiparallel; higher energy level).
  • This establishes the ground state distribution in the presence of the magnetic field (net zero energy).
  • An excited state distribution (net high energy) is achieved by an uneven population of the two levels, for example, when more of the hydrogen spins are aligned antiparallel than parallel.
  • Such spin excitation is accomplished by introduction of energy from an external source, e.g., with a pulse of radiation in the radio frequency ("RF") region.
  • the net effect of spin excitation is to produce a temporary net magnetization in the sample.
  • the net magnetization decays or relaxes to the ground state by various relaxation processes (commonly longitudinal relaxation or T 1 ; transverse relaxation or T 2 ; see below) in the absence of continuous permanent application of pulses. It is the decay of magnetization that is converted to signals observed in MRI.
  • T 1 longitudinal relaxation
  • T 2 transverse relaxation
  • [H] is the concentration of water hydrogens
  • k is a constant that includes instrument- specific- and motion-related factors
  • Ti and T 2 are the respective longitudinal and transverse proton relaxation times
  • TR is the pulse repetition time
  • TE is the echo delay time.
  • TR and TE are extrinsic instrument selectable variables which are uniquely selected for the pulse sequence applied during the imaging experiment.
  • Ti and T 2 have inverse and reciprocal effects on image intensity; hence, image intensity may be increased either by shortening the longitudinal relaxation time Ti or lengthening the transverse relaxation time T 2 .
  • MR images are typically displayed on a gray scale with the color black representing the lowest measured intensity and white representing the highest measured intensity.
  • T 2 is the transverse relaxation time, or spin-spin relaxation time, and is one of several contributions to T 2 *.
  • the signal amplitude recorded for any given scan is proportional to the number of spins that have decayed (or relaxed) back to equilibrium in the time period between successive scans.
  • regions with rapidly relaxing spins i.e. spins having short Ti values
  • the measured intensities of the regions with long T 2 and short Ti will reflect the spin density, i.e., that region's water content.
  • Regions with long Ti values as compared to the repetition time (time between scans, TR), will progressively lose signal (i.e., signal will broaden, "flatten out”) until a steady state condition is reached when these regions will appear dark.
  • Clinical MRI takes advantage of the fact that water relaxation characteristics (e.g., Ti and T 2 values) vary between tissues. This inherent differential tissue relaxation provides image contrast which allows tissue identification. Additionally, the MRI experiment can be set up so that regions of a sample with short Ti values or long T 2 values are preferentially enhanced. Such designed MRI protocols are known as Ti-weighted and T 2 - weighted imaging protocols. For a description of the MRI experimental process, see R. Hashemi, MRI: The Basics, 2nd ed., Lippincott, Williams & Wilkins, 2004 and V. Runge, The Physics of Clinical MR. Thieme, NY, 2005.
  • water relaxation characteristics e.g., Ti and T 2 values
  • Paramagnetic contrast agents serve to modulate Ti and/or T 2 values.
  • MRI contrast agents comprise compounds of both paramagnets and superparamagnets such as transition metal-chelate compounds and nitroxyl spin labeled compounds (paramagnets) and iron oxide suspensions (superparamagnets) which act as potent relaxation enhancement agents, i.e., they decrease the Ti and T 2 relaxation times of nearby proton spins.
  • the relaxivity of a contrast agent is dominated by the selection of the metal atom.
  • Gadolinium (Gd 3+ , f 7 ), iron (Fe 3+ , d 5 ) and manganese (Mn 2+ , d 5 ) are the most commonly studied.
  • the mechanism of Ti relaxation is generally a through-space dipole-dipole interaction between the unpaired electrons of the paramagnet and the bulk water molecules that are in fast exchange with inner sphere (IS) water molecules.
  • IS inner sphere
  • the relaxation rate constant, R 1 has several components of which the inner sphere (IS) pathway to longitudinal relaxation rate enhancement is dominant.
  • the longitudinal IS proton relaxation rate, X ⁇ is expressed as follows 55.5(7;. + r.)
  • [M] is the concentration of paramagnetic metal ions
  • q is the number of inner sphere water molecules, i.e., water molecules directly bound to the metal ion
  • T lm is longitudinal proton relaxation time
  • T M is the water exchange lifetime, i.e., lifetime of association of the water molecule with the metal center.
  • the relaxivity of a contrast agent is derived from the change in relaxation rate constant ( ⁇ R) induced by a known concentration of the contrast agent ([M]), i.e., ⁇ Ri/[M] (or AR 2 Z[M]). Relaxivities are typically expressed in units of mM ⁇ sec "1 .
  • T M The water exchange lifetime, represents the lifetime of the water proton (or water molecule) in the gadolinium chelate complex (or the rate of exchange with the bulk water). It plays a dual role in its contribution to the relaxivity; hence, its contribution to relaxivity is more complicated and must be assessed with care.
  • complexes with labile water molecules demonstrate high relaxivities ( ⁇ 4 mM ⁇ sec '1 ).
  • high relaxivities ⁇ 4 mM ⁇ sec '1
  • Gd(III) can be chelated with any of a number of substances such as diethylenetriamine-pentaacetic acid (“DTPA”), 1,4,7,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid (“DOTA”), and derivatives thereof. See, U.S. Patent Nos.
  • the macrocyclic analog, Gd-DOTA complex, based on the tetraazamacrocycle cyclen, is conformationally more rigid, and at physiological pH, possesses very slow dissociation kinetics and is therefore presumed safer.
  • Regions associated with a metal ion (Gd(III)) having proximate water molecules appear bright in an MR image, while the normal aqueous solution appears as dark background when the time between successive scans in the experiment is short, i.e., in a Ti weighted image.
  • Cyclen 1,4,7,10-tetraazacyclododecane
  • the tris-N- carboxymethylated tetraazamacrocycle, 4,7,10-triscarboxymethyl- 1 ,4,7, 10- tetraazacyclododecane, D03A is a ligand by itself and also a key intermediate which can be variously derivatized, either at the free macrocyclic nitrogen or on the ethylene backbone, for formation of a range of ligands for several applications.
  • Various metal complexes of D03A are useful for imaging and therapy.
  • the relaxivities of the Gd-based agents described above are about 4 mM ⁇ sec "1 in aqueous solution and in vivo.
  • no diaqua or triaqua agents have been developed because of the expectation, based on data from other metal complexes with increased inner sphere water molecules, that they may be kinetically unstable with respect to acid or cation-mediated dissociation in vivo.
  • diaqua or triaqua compound with physiologically endogenous anions such as phosphate, carbonate or lactate may result in displacement of the inner sphere water molecules; hence a decrease in relaxivity.
  • the present invention is directed to a coordinated or uncoordinated tetraazamacrocycle having 12, 13 or 14 ring atoms.
  • this macrocycle contains 4 ring nitrogen atoms and 8-10 ring carbon atoms where each ring nitrogen atom is separated from another ring nitrogen atom by at least two ring carbon atoms.
  • the macrocycle is also substituted by at least three groups that are ionizable at physiological pH, provided that a di- aqua macrocyclic complex formed with a lanthanide metal having a +3 charge has an overall net charge of -1.
  • Three of the ionizable groups are capable of coordinating with a single lanthanide metal when the macrocycle forms a lanthanide complex, and are independently carboxyl, phosphorous-oxo acid or sulfur-oxy acid groups; the three ionizable groups being bonded, directly or indirectly, to two or three ring atoms of the macrocycle.
  • each of these three ionizable groups is separated from the ring atom to which it is bonded by no more than three atoms.
  • two ionizable groups are attached to the macrocycle via a single macrocycle atom.
  • two ionizable groups may both be substituents on a single chain connected to the macrocycle atom or, in the case of a macrocycle carbon atom having two bonds available for attachment of substituent groups, two ionizable groups may be substituents on separate chains connected to the macrocycle atom.
  • the number and charge of the ionized non-coordinating groups will be the number necessary to result in an overall net charge of -1.
  • the tetraazamacrocyclic compounds of the present invention (sometimes referred to herein as macrocyclic compounds or macrocycles) enable production of improved contrast agents for use in MR imaging due to increased relaxivity.
  • the macrocyclic compounds tend to form stable di-aqua complexes with lanthanide metals, typically gadolinium.
  • the macrocycles of the present invention comprise 12-, 13-, or 14- ring members and bear at least three groups that are ionizable at physiological pH, provided that a di-aqua macrocyclic complex formed with a lanthanide metal having a +3 charge has an overall net charge of -1.
  • the ionized coordinating groups are mono-anionic (e.g., -C(O)(OH) groups) or di-anionic (e.g., -P(OH)2, -P(O)(OH)2, and - S(O)(OH)2 groups)
  • the number and charge of the ionized non-coordinating groups will be the number necessary to result in an overall net charge of -1.
  • the sum of the charges of the three ionized coordinating groups may be -3, -4, -5, or -6 depending on the selection of the ionized coordinating groups.
  • the non-coordinating, ionizable group capable of generating the negative charge is selected from carboxyl, phosphorous-oxo acid, sulfur-oxy acid, phenolic -OH, thiophenolic -SH, or acetylacetonyl -CH(EWG)- groups separated from a ring carbon or nitrogen atom of the macrocycle by four to nine atoms; wherein EWG is an electron withdrawing group.
  • the non-coordinating group capable of generating the positive charge is typically a group containing a primary, secondary or tertiary amine that can be protonated at physiological pH.
  • the non-coordinating, ionizable group may either be a substituent on a single chain connected to a macrocycle atom or a substituent on a chain also containing one of the coordinating ionizable groups.
  • Table I provides an exemplary list of substituent combinations of coordinating and non-coordinating groups for the macrocycles of the present invention that are capable of producing a lanthanide complex of the present invention having an overall net charge of -1.
  • three of the ionizable groups function to coordinate a single lanthanide metal and are carboxyl groups while a fourth ionizable group imparts a single negative charge on the complex, at physiological pH, but does not participate in the coordination of the lanthanide.
  • the macrocycle corresponds to Formula (I)
  • mi through m 4 are independently 1 or 2, provided the sum of mi through m 4 is 4-6. In one embodiment, the sum of mi through m 4 is 4 or 5; thus, the macrocyclic ring contains 12 or 13 ring atoms, respectively.
  • n is 2 to 8, preferably 2, 3 or 4, where each R is independently substituted hydrocarbyl, optionally substituted by R A , provided, in combination, the macrocycle is substituted by at least three groups that are ionizable at physiological pH.
  • Three of the ionizable groups are capable of coordinating with a single lanthanide metal when the macrocycle forms a lanthanide complex, and are independently carboxyl, phosphorous-oxo acid or sulfur-oxy acid groups, the three ionizable groups being bonded, directly or indirectly, to two or three ring atoms of the macrocycle.
  • each of these three ionizable groups is separated from the ring atom to which it is bonded by no more than three atoms.
  • two groups are attached to the macrocycle via a single macrocycle atom.
  • two ionizable groups may both be substituents on a single hydrocarbyl chain connected to the macrocycle atom, i.e., a single hydrocarbyl group is substituted with two ionizable groups, or, in the case of a macrocycle carbon atom having two bonds available for attachment of hydrocarbyl groups, two ionizable groups may be substituents on separate hydrocarbyl groups connected to a single macrocycle carbon atom.
  • the additional ionizable groups are non-coordinating groups that can form anions or cations at physiological pH.
  • the non-coordinating groups that form anions are selected from carboxyl, phosphorous-oxo acid, sulfur-oxy acid, phenolic -OH, thiophenolic -SH, or acetylacetonyl -CH(EWG)- groups separated from a ring carbon or nitrogen atom of the macrocycle by four to nine atoms; wherein EWG is an electron withdrawing group.
  • the non-coordinating groups that form cations are non-coordinating amine groups, i.e. primary, secondary or tertiary amines, that can be protonated at physiological pH.
  • each of the at least four ionizable groups is a substituent of a separate hydrocarbyl group bonded to a macrocyclic ring carbon or nitrogen atom.
  • one of the three coordinating ionizable groups and a fourth non-coordinating ionizable group are both bonded to the same macrocyclic ring atom via a single hydrocarbyl group.
  • one of the three coordinating ionizable groups and a fourth non-coordianting ionizable group are both bonded to the same macrocyclic ring atom via a single hydrocarbyl group, and the other two coordinating ionizable groups are both bonded to the same macrocyclic ring atom via a separate hydrocarbyl group,
  • R A is independently a linker chemically linking one or more bio-directing modifiers to the macrocycle, Ci_2o alkyl, or aryl, optionally substituted by one or more aryl, Ci_ 20 alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, polypeptides, phosphorous- oxo acid, sulfur-oxy acid,
  • each macrocyclic carbon atom may be substituted by up two substituents and each macrocyclic ring nitrogen atom may be substituted with one substituent.
  • each A is independently a linker chemically linking one or more bio-directing modifiers to the macrocycle, Ci_ 2 o alkyl, or aryl, optionally substituted by one or more aryl, Ci_ 2 o alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, polypeptides, phosphorous-oxo acid, sulfur-oxy acid, hydroxyl, oxy, ether, polyether, C4-20 carbohydrate, mercapto or thiol.
  • the at least three ionizable groups of macrocycles of Formula (I) can be categorized by their ability to coordinate a lanthanide metal thereby forming a metal complex (sometimes simply referred to as a "complex") at physiological pH. Whether a particular ionizable group of the present invention will coordinate a lanthanide metal is largely a function of (1) the identity of the ionizable group itself, and (2) the number of atoms separating the ionizable group from a macrocyclic ring atom.
  • three ionizable groups coordinate with a single lanthanide metal.
  • the three ionizable groups are separated from a macrocyclic ring atom by a number of atoms such that a 5-, 6- or 7-membered ring forms comprising the lanthanide metal and the macrocyclic ring atom.
  • each group in order for these three ionizable groups to coordinate the metal, each group must have a -OH moiety that is (1) ionizable at physiological pH and (2) be part of a group, e.g., a carboxyl group, that is separated from a macrocyclic ring atom by no more than three atoms.
  • the ionizable group When the ionizable group is attached via a macrocyclic nitrogen, there must be at least one atom, e.g., a methylene group, between the macrocyclic nitrogen and the ionizable group.
  • the functional groups having an ionizable -OH moiety are selected from carboxyl, phosphorous-oxo acid and sulfur-oxy acid groups, and combinations thereof.
  • carboxyl group As an example, to coordinate the lanthanide, the carboxyl group is separated from the macrocyclic ring atom by no more than three atoms, i.e., the -O " moiety of the carboxyl group is separated from a macrocyclic ring atom by no more than four atoms.
  • An exemplary structure is illustrated below:
  • the carboxyl group (-C(O)O " ) is separated from the macrocyclic ring nitrogen by two carbon atoms and the -O " moiety of the carboxyl group is separated from the macrocyclic ring nitrogen by three atoms.
  • an ionizable group and the atoms through which the ionizable group is bonded to a macrocyclic ring atom, and any substituents thereof, are sometimes referred to as an "arm" of the macrocycle.
  • the macrocycles of the present invention have at least three coordinating arms, each coordinating arm comprising one of the three coordinating ionizable groups.
  • the ionizable -OH moiety of the carboxyl, phosphorous-oxo acid and sulfur-oxy acid groups is generally not separated from a macrocyclic ring atom by more than four atoms, it is typically separated by fewer than three atoms.
  • the ionizable -OH moiety of the carboxyl, phosphorous-oxo acid and sulfur-oxy acid group is separated by two atoms; e.g., a carboxyl moiety attached to a macrocyclic ring atom via a methylene group.
  • the non-coordinating ionizable group capable of forming an anionic group is preferably (1) ionizable at physiological pH and (2) separated from the macrocyclic ring atom to which it is attached, either directly or indirectly, by a sufficient number of atoms such that the ionizable group does not coordinate a metal in the macrocycle under conditions in which such ionizable group is in ionized form.
  • the ionizable group capable of forming an anion is selected from carboxyl, phosphorous-oxo acid, sulfur-oxy acid, phenolic -OH, thiophenolic -SH, or acetylacetonyl -CH(EWG)- groups, where the groups are separated from a macrocyclic ring atom by four to nine atoms.
  • the ionizable moiety for the carboxyl, phosphorous-oxo acid, sulfur-oxy acid, and phenol groups is the -OH moiety, while the ionizable moiety for a thiophenol group is -SH.
  • the ionizable -CH- moiety is alpha to both of the carbonyl carbon atoms and substituted by an electron withdrawing group (EWG).
  • EWG electron withdrawing group
  • typical electron withdrawing groups include, but are not limited to, hydroxyl, cyano (-CN), fluoro, -CF 3 , -CF 2 CF 3 , nitro (-NO 2 ), alkylester (-CO 2 R), and -CF 2 CO 2 R where R is Ci_6 alkyl.
  • the electron withdrawing group is selected from cyano, nitro or -CF 3 .
  • the electron withdrawing group is -CF 3 .
  • the non-coordinating ionizable group capable of forming a cationic group is a group that can be protonated at physiological pH.
  • the ionizable group capable of forming a cation is selected from primary, secondary, or tertiary amine groups.
  • the ionizable amine group is a substituent on a substituted hydrocarbyl moiety attached to the macrocycle, the hydrocarbyl group optionally comprising one or more hydrophilic imparting moieties, e.g., ethers, polyethers, ketones, alcohols, polyalcohols, carbohydrates and polypeptides.
  • n is 3 where a fourth ionizable group is bonded to one of the three coordinating arms.
  • one of the R substituents comprises one of the three coordinating ionizable groups and a fourth non-coordinating ionizable group.
  • n is 4 and a fourth ionizable group is bonded to a macrocyclic ring atom, such ring atom not being bonded to any of the three coordinating arms.
  • the macrocycle will have at least four arms, three coordinating arms and at least one non-coordinating arm.
  • n is 2 and one of the three coordinating ionizable groups and a fourth ionizable group are both bonded to the same macrocyclic ring atom via a single hydrocarbyl group, and the other two coordinating ionizable groups are both bonded to the same macrocyclic ring atom via a separate hydrocarbyl group,
  • each A and/or R A be a linker chemically linking one or more bio-directing modifiers to the macrocycle and/or be a substituent selected to positively impact stability and/or biodistribution.
  • each A and/or R A is selected from the group consisting of Ci_2o alkyl or aryl, optionally substituted by one or more aryl, Ci_2o alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, polypeptides, phosphorous-oxo acid, sulfur-oxy acid, hydroxyl, oxy, ether, polyether, C 4 _ 2 o carbohydrate, mercapto or thiol.
  • each A and/or R A may be aryl or Ci_6 alkyl optionally substituted with one or more aryl, keto, amido and oxy.
  • each A and/or R A may be methyl.
  • one or more of the A and/or R A substituents may be a linker chemically linking one or more bio-directing modifiers to the macrocycle.
  • the linker may be modified or synthesized such that it bonds to multiple bio- directing modifiers and/or affects the biodistribution of the macrocycle.
  • the linker may comprise a C 4- C 2O carbohydrate moiety, the carbohydrate moiety having the capacity to bind one or more bio-directing modifiers through ether linkages.
  • the carbohydrate moiety increases the water solubility of the macrocycle thereby affecting biodistribution.
  • the linker is selected from the group consisting Of C 1-10 alkylene, oxygen, sulfur, keto (-C(O)-), amino (-NH-), amido (-C(O)NH-), urea (-NHC(O)NH-), thiourea (-NHC(S)NH-), ester (-C(O)O-), polyoxo (e.g., -0-CH 2 CH 2 -O- CH 2 CH 2 -O-), polyhydroxy (e.g., carbohydrates), and peptides, the alkylene, amino, amido, urea, and thiourea groups being optionally substituted with aryl, Ci_7 alkyl, Ci_7 hydroxyalkyl or Ci_ 7 alkoxyalkyl.
  • the linker is selected from the group consisting Of C 1-10 alkylene, oxygen, sulfur, keto, amino, amido, thiourea, ester, C 4 -C 2 O carbohydrate, the alkylene, amino, amido, and thiourea groups being optionally substituted with aryl, Ci_ 7 alkyl, Ci_ 7 hydroxyalkyl or Ci_ 7 alkoxyalkyl.
  • the linker may be selected from a more restrictive group, e.g., amido, thiourea, monosaccharides (e.g., hexoses and pentoses) and disaccharides (e.g., sucrose).
  • the linker comprises other than a urea linkage.
  • the bio-directing modifier(s) are selected from those moieties that restrict the complex to the vascular compartment. Generally, to achieve the restriction of the biodistribution of the complex to the vascular compartment, it is necessary to increase the molecular weight of the complex.
  • the bio-directing modifiers are 10-30 KD in weight and are selected from PEG(s), carbohydrates, and polypeptides. In a preferred embodiment, the bio-directing modifier(s) are PEG.
  • the macrocycle corresponds to Formula (II)
  • mi through m 4 are independently 1 or 2, provided the sum of mi through m 4 is 4-6;
  • p is an integer from 0 to 14;
  • R1-R3 are independently substituted hydrocarbyl moieties, optionally substituted by R A , in which the three hydrocarbyl moieties are substituted by first, second and third ionizable groups, respectively, each of the ionizable groups being carboxyl groups with each of the three ionizable groups being bonded, directly or indirectly, to different ring atoms of the macrocycle, provided each of the three ionizable groups are separated from the ring atoms to which they are bonded by no more than three atoms;
  • R 4 is a substituted hydrocarbyl moiety, optionally substituted by R A , in which the moiety is substituted by a fourth ionizable group selected from carboxyl, phenolic -OH, thiophenolic -SH, or acetylacetonyl -CH(EWG)- groups separated from a ring nitrogen atom of the macrocycle by four to nine atoms, wherein EWG is an electron withdrawing group; and
  • each A and R A is independently a linker chemically linking one or more bio-directing modifiers to the macrocycle, Ci_2o alkyl, or aryl, optionally substituted by one or more aryl, Ci_2o alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, polypeptides, phosphorous-oxo acid, sulfur-oxy acid, hydroxyl, oxy, ether, polyether, C 4-2 O carbohydrate, mercapto or thiol.
  • each of the four ionizable arms (R) is bonded to a separate macrocyclic ring atom.
  • each of the ionizable arms is bonded to a separate ring nitrogen atom.
  • each macrocyclic ring nitrogen atom is substituted by one of the ionizable arms.
  • the macrocycle corresponds to Formula (III):
  • p is an integer from 0 to 8.
  • x is an integer from 0 to 4.
  • R1-R3 are independently substituted hydrocarbyl moieties, optionally substituted by R A , in which the three moieties are substituted by first, second and third ionizable groups, respectively, each of the ionizable groups being independently selected from the group consisting of carboxyl, phosphorous- and sulfur-oxy acid groups with each of the three ionizable groups being bonded, directly or indirectly, to different ring atoms of the macrocycle, provided each of the three ionizable groups are separated from the ring atoms to which they are bonded by no more than three atoms;
  • R 4 is a substituted hydrocarbyl moiety, optionally substituted by R A , in which the moiety is substituted by a fourth ionizable group selected from carboxyl, phosphorous-oxo acid, sulfur-oxy acid, phenolic -OH, thiophenolic -SH, or acetylacetonyl -CH(EWG)- groups separated from
  • R x is a substituted hydrocarbyl moiety, optionally substituted by R A , in which the moiety is substituted by additional ionizable, non-coordinating groups selected from: (iii) carboxyl, phosphorous-oxo acid, sulfur-oxy acid, phenolic -OH, thiophenolic -SH, or acetylacetonyl -CH(EWG)- groups, where the ionizable group that forms an anion is separated from a ring carbon or nitrogen atom of the macrocycle by four to nine atoms; where EWG is an electron withdrawing group, or (iv) amine groups; and,
  • each A and R A is independently a linker chemically linking one or more bio-directing modifiers to the macrocycle, Ci_ 2 o alkyl, or aryl, optionally substituted by one or more aryl, Ci_2o alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, polypeptides, phosphorous-oxo acid, sulfur-oxy acid, hydroxyl, oxy, ether, polyether, C4-20 carbohydrate, mercapto or thiol.
  • the macrocycles correspond to Formula (IV):
  • p is an integer from 0 to 4.
  • x is an integer from 0 to 4.
  • X 1 -X 3 are independently methylene, ethylene or propylene, optionally substituted by R A ;
  • X 4 is an alkylene group of length sufficient to separate the attached ring nitrogen atom from Z 4 by the required number of atoms, optionally substituted by R A ;
  • Zi-Z 3 are independently carboxyl, phosphorous-oxo acid or sulfur-oxy acid groups;
  • Z 4 is a carboxyl, phosphorous-oxo acid, sulfur-oxy acid, phenol, thiophenol, or acetylacetonyl group; provided that if Z 4 is a phenol, thiophenol, or acetylacetonyl group, then the group may be optionally substituted by R A ;
  • R x is a substituted hydrocarbyl moiety, optionally substituted by R A , in which the moiety is substituted by additional ionizable, non-coordinating groups selected from: (i) carboxyl, phosphorous-oxo acid, sulfur-oxy acid, phenolic -OH, thiophenolic -SH, or acetylacetonyl -CH(EWG)- groups, where the ionizable group that forms an anion is separated from a ring carbon or nitrogen atom of the macrocycle by four to nine atoms; where EWG is an electron withdrawing group, or (ii) amine groups; and
  • each A and R A is independently a linker chemically linking one or more bio-directing modifiers to the macrocycle, Ci_2o alkyl, or aryl, optionally substituted by one or more aryl, Ci_2o alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, polypeptides, phosphorous-oxo acid, sulfur-oxy acid, hydroxyl, oxy, ether, polyether, C 4 _ 2 o carbohydrate, mercapto or thiol.
  • Z 4 is carboxyl, phosphorous-oxo acid, or sulfur-oxy acid
  • X 4 is butylene or pentylene.
  • Z 4 is phenolic -OH, thiophenolic -SH, or acetylacetonyl -CH(EWG)- groups, it is currently preferred that X 4 is ethylene or propylene.
  • X 1 -X 3 are methylene or ethylene, optionally substituted by R A .
  • each OfZi-Z 3 is carboxyl.
  • the macrocycle Prior to use in a diagnostic procedure, e.g., MRI, the macrocycle is complexed with a lanthanide metal.
  • lanthanide metals include cerium, praseodymium, neodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, and ytterbium.
  • the lanthanide metal is gadolinium or dysprosium, more preferably, gadolinium.
  • the four ionizable groups of the macrocycle deprotonate.
  • the three coordinating ionizable groups coordinate the lanthanide metal, while the fourth ionizable group does not coordinate the metal.
  • the metal is coordinated by the macrocyclic ring nitrogen atoms and two inner sphere water molecules.
  • the resulting complex possesses a high relaxivity in part because the pKa of the fourth ionizable group is more acidic than that of the coordinated inner sphere water molecules resulting in a bis-aqua complex bearing two exchangeable inner-sphere water molecules.
  • any of the macrocycles of Formulae (I) through (IV) can coordinate a lanthanide metal thereby forming a complex.
  • the complex has the structure:
  • M is a lanthanide metal
  • Z 4 is a carboxyl, phenol, thiophenol, or acetylacetonyl group.
  • the complex has the following structure at physiological pH:
  • the macrocycles of the present invention can be synthesized as described below.
  • coordinating and non-coordinating ionizable arms substituted on the macrocyclic nitrogen atoms are synthesized by controlled multistep alkylation of a polyazamacrocycle, such as cyclen, in a process as shown in General Scheme A:
  • chelate designs may be based on a macrocycle where the attachment of coordinating and non-coordinating ionizable side arms are not only attached via the macrocyclic nitrogen, but also attached at a macrocyclic carbon. Natural, or unnatural, amino acids make excellent building blocks for such species. For instance, a carbon-centered side-arm derived macrocycle could be prepared as shown below in General Scheme B.
  • a base scaffold exhibiting three masked ionizable groups can be prepared. Ring closure with a suitable, masked ionizable non-coordinating group produces the protected macrocycle as shown below.
  • Macrocycles of the present invention having one or more bio-directing modifiers may be synthesized, for example, as shown in General Scheme C.
  • the complexes of the present invention can be formulated into diagnostic compositions for enteral or parenteral administration.
  • These compositions contain an effective amount of the paramagnetic ion complex along with conventional pharmaceutical carriers and excipients appropriate for the type of administration contemplated.
  • parenteral formulations advantageously contain a sterile aqueous solution or suspension of from about 0.05 to 1.0M of a paramagnetic ion complex according to the present invention.
  • Preferred parenteral formulations have a concentration of paramagnetic ion complex of 0.1M to 0.5M.
  • Such solutions also may contain pharmaceutically acceptable buffers, such as sodium, calcium, or zinc salts of the macrocycle of the present invention, and, optionally, electrolytes such as sodium chloride.
  • compositions advantageously may contain one or more physiologically acceptable, non-toxic cations in the form of a gluconate, chloride or other suitable organic or inorganic salt.
  • physiologically acceptable, non-toxic cations include sodium ions, calcium ions, magnesium ions, copper ions, zinc ions and the like. Calcium ions are preferred.
  • Parenteral compositions can be injected directly or mixed with a large volume parenteral composition for systemic administration.
  • Formulations for enteral administration may vary widely, as is well-known in the art.
  • such formulations are liquids which include an effective amount of the paramagnetic ion complex in aqueous solution or suspension.
  • Such enteral compositions may optionally include buffers, surfactants, thixotropic agents, and the like.
  • Dosage and regimens for the administration of the pharmaceutical compositions of the invention can be readily determined by those with ordinary skill in diagnosing or treating disease. It is understood that the dosage of the complex will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. For any mode of administration, the actual amount of complex delivered, as well as the dosing schedule necessary to achieve the advantageous effects described herein, will also depend, in part, on such factors as the bioavailability of the complex, the disorder being treated or diagnosed, the desired therapeutic or diagnostic dose, and other factors that will be apparent to those of skill in the art.
  • the dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect the desired therapeutic or diagnostic response in the animal over a reasonable period of time.
  • 0.1 mmole contrast agent/kg bodyweight is considered a single dose.
  • An agent of higher relaxivity may be expected to use less (in comparable procedures), the same (to take advantage of the potential higher sensitivity for lesions a more potent agent may reveal), or even more (if safety testing proves the agent biocompatible at higher doses).
  • the compounds described herein may have asymmetric centers.
  • Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic form.
  • Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
  • oxo acid or "oxy acid” as used herein utilizes the International Union of Pure and Applied Chemistry (IUPAC) nomenclature contained in the IUPAC Blue Book, Rigaudy, J. and Klesney, S.P. Nomenclature of Organic Chemistry; pages 234, 397; Pergammon: Oxford, 1979.
  • oxo acid or "oxy acid” are used in referring to the appropriate corresponding oxygenated phosphorus-, sulfur- and carbon-based acids, such as -P(O)(OH) 2 as phosphonic or -C(O)OH as carboxylic acids.
  • alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.
  • amido as used herein includes substituted amido moieties where the substituents include, but are not limited to, one or more of aryl and Ci_ 2 o alkyl, each of which may be optionally substituted by one or more aryl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, Ci_2o alkyl, phosphorous-oxo acid, sulfur-oxy acid, hydroxyl, oxy, mercapto, and thio substituents.
  • substituents include, but are not limited to, one or more of aryl and Ci_ 2 o alkyl, each of which may be optionally substituted by one or more aryl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, Ci_2o alkyl, phosphorous-oxo acid, sulfur-oxy acid, hydroxyl, oxy, mercapto, and thio substituents.
  • amino as used herein includes substituted amino moieties where the substituents include, but are not limited to, one or more of aryl and Ci_ 2 o alkyl, each of which may be optionally substituted by one or more aryl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, Ci_2o alkyl, phosphorous-oxo acid, sulfur-oxy acid, hydroxyl, oxy, mercapto, and thio substituents.
  • substituents include, but are not limited to, one or more of aryl and Ci_ 2 o alkyl, each of which may be optionally substituted by one or more aryl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, Ci_2o alkyl, phosphorous-oxo acid, sulfur-oxy acid, hydroxyl, oxy, mercapto, and thio substituents.
  • aryl or “ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl.
  • chelate refers to a macrocycle of the invention, e.g., Formula (I), which is capable of binding of complexing or coordinating a metal. Thus, the chelates of the present invention are not complexed with a metal.
  • complex refers to a macrocycle of the invention, e.g. Formula (I), complexed or coordinated with a metal.
  • halogen or halo as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
  • hydrocarbyl as used herein describes an organic compound or radical consisting exclusively of the elements carbon and hydrogen.
  • This moiety includes alkyl, alkenyl, alkynyl, and aryl moieties. This moiety also includes alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, this moiety preferably contains 1 to 20 carbon atoms
  • protecting group denote a group capable of protecting a reactive group, e.g., a free hydroxyl group ("protected hydroxyl"), amine group (“protected amine”), sulfhydryl group (“protected sulfhydyl”) etc., which, subsequent to the reaction for which protection is employed, may be removed without disturbing the remainder of the molecule.
  • a variety of protecting groups and the synthesis thereof may be found in Protective Groups in Organic Synthesis by T. W. Greene, John Wiley and Sons, 1981, or Fieser & Fieser.
  • Example 1 Gadolinium [l,4,7,10-tetraazacyclododecane-l-(3- propanato)-4,7, 10-triacetato(4-)
  • Gadolinium [l,4,7,10-tetraazacyclododecane-l-(3-propanato)-4,7,10- triacetato(4-)
  • a sample of the chelate (0.2g, 0.5mmole) was dissolved in water. To this was added gadolinium oxide (0.087g, 0.25mmole). The mixture was heated to 65°C overnight with stirring. The mixture was cooled to room temperature and pH of the solution was adjusted with NaOH (IM, just a few drops) to pH of 8. The resulting mixture was filtered, 0.2 ⁇ m, and submitted for relaxivity and ICP testing.
  • Example 2 Gadolinium [l,4,7,10-tetraazacyclododecane-l-(4- butanato)-4,7,10-triacetato(4-)
  • the ethyl ester (l .Og, 1.4mmoles) was saponified using aqueous sodium hydroxide (0.057g, 1.5mmoles dissolved in 5mL water) in methanol (5mL). After stirring overnight, under argon and at room temperature, the mixture was evaporated to a foam. Yield 0.9g (91%) HPLC-MS shows the material to be >95% desired sodium salt.
  • Gadolinium [l,4,7,10-tetraazacyclododecane-l-(4-butanato)-4,7,10- triacetato(4-)
  • a sample of the chelate (0.2g, 0.5mmole) was dissolved in water.
  • gadolinium oxide (0.087g, 0.25mmole).
  • the mixture was heated to 65°C overnight with stirring.
  • the mixture was cooled to room temperature and pH of the solution was adjusted with NaOH (IM, just a few drops) to pH of 8.
  • the resulting mixture was filtered, 0.2 ⁇ m, and submitted for relaxivity and ICP testing.
  • Example 3 Gadolinium [l,4,7,10-tetraazacyclododecane-l-(5- pentanato)-4,7,10-triacetato(4-)
  • a methanol solution (ImL) of the sodium tert-butyl 2,2',2"-(10-(5-ethoxy-5-oxopentyl)- l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triacetate bromide (1.0Og, 1.3mmoles) was treated with a water-methanol (5mL:5mL) of sodium hydroxide (0.056g, 1.4mmoles). The mixture was stirred overnight, under argon, at room temperature. HPLC-MS showed that the reaction was greater 95% complete. Acetone (2OmL) was added to precipitate the excess sodium hydroxide. The mixture was filtered and the filtrate evaporated to a solid.
  • Gadolinium [l,4,7,10-tetraazacyclododecane-l-(5-pentanato)-4,7,10- triacetato(4-)
  • a sample of the chelate (0.2g, 0.4mmole) was dissolved in water. To this was added gadolinium oxide (0.087g, 0.25mmole). The mixture was heated to 65°C overnight with stirring. The mixture was cooled to room temperature and pH of the solution was adjusted with NaOH (IM, just a few drops) to pH of 8. The resulting mixture was filtered, 0.2 ⁇ m, and submitted for relaxivity and ICP testing.
  • the gadolinium complexes of DO3 A-propanoate, -butanoate and -pentanoate have been prepared in situ. Relaxivity measurements at low (pH 2), intermediate (pH 6 to 8) and high pH (pH 10) confirm our theory on the relationship between a pendant anionic charge and MRCM potency of di-aqua gadolinium complexes. The pH-dominated relaxivity behavior of our complexes is shown below:

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Abstract

La présente invention concerne des composés tétraazamacrocycliques et des complexes de lanthanide de ceux-ci utiles comme agents de contraste MRI ayant une relaxivité améliorée.
PCT/US2008/061078 2007-04-26 2008-04-22 Complexes de lanthanide insaturés de manière coordonnée à relaxivité élevée WO2008134289A2 (fr)

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WO2012151539A3 (fr) * 2011-05-05 2013-01-03 New York University Capsule de complexe lanthanoïde et agents de contraste particulaire, leurs procédés de fabrication et d'utilisation
WO2015142583A1 (fr) * 2014-03-17 2015-09-24 The Board Of Regents Of The University Of Texas System Nouveaux agents de contraste à base de gadolinium pour une détection sensible de zn2+ par irm
US10093741B1 (en) 2017-05-05 2018-10-09 Fusion Pharmaceuticals Inc. IGF-1R monoclonal antibodies and uses thereof
US11191854B2 (en) 2017-05-05 2021-12-07 Centre For Probe Development And Commercialization Pharmacokinetic enhancements of bifunctional chelates and uses thereof
CN114573609A (zh) * 2022-03-07 2022-06-03 桂林理工大学 一种基于不对称双核镝配合物的单分子磁体及其制备方法
US11433148B2 (en) 2017-05-05 2022-09-06 Centre For Probe Development And Commercialization IGF-1R monoclonal antibodies and uses thereof

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WO2012151539A3 (fr) * 2011-05-05 2013-01-03 New York University Capsule de complexe lanthanoïde et agents de contraste particulaire, leurs procédés de fabrication et d'utilisation
US8865129B2 (en) 2011-05-05 2014-10-21 New York University Lanthanoid complex capsule and particle contrast agents, methods of making and using thereof
US9579404B2 (en) 2011-05-05 2017-02-28 New York University Lanthanoid complex capsule and particle contrast agents, methods of making and using thereof
WO2015142583A1 (fr) * 2014-03-17 2015-09-24 The Board Of Regents Of The University Of Texas System Nouveaux agents de contraste à base de gadolinium pour une détection sensible de zn2+ par irm
US10207013B2 (en) 2014-03-17 2019-02-19 The Board Of Regents Of The University Of Texas Systems Gadolinium-based contrast agents for sensitive detection of Zn2+ with MRI
US11097017B2 (en) 2014-03-17 2021-08-24 The Board Of Regents Of The University Of Texas System Gadolinium-based contrast agents for sensitive detection of Zn2+with MRI
US10093741B1 (en) 2017-05-05 2018-10-09 Fusion Pharmaceuticals Inc. IGF-1R monoclonal antibodies and uses thereof
US11191854B2 (en) 2017-05-05 2021-12-07 Centre For Probe Development And Commercialization Pharmacokinetic enhancements of bifunctional chelates and uses thereof
US11433148B2 (en) 2017-05-05 2022-09-06 Centre For Probe Development And Commercialization IGF-1R monoclonal antibodies and uses thereof
CN114573609A (zh) * 2022-03-07 2022-06-03 桂林理工大学 一种基于不对称双核镝配合物的单分子磁体及其制备方法
CN114573609B (zh) * 2022-03-07 2024-02-06 桂林理工大学 一种基于不对称双核镝配合物的单分子磁体及其制备方法

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