MXPA97009787A - Chelating polymers as agents of contrast for formation of image - Google Patents

Abstract

The invention provides polymeric polychelators containing repeating polymer units of the form [L-Ch-LB] (wherein Ch is a polyvalent or polyvalent chelating moiety; L is an amide oester bond; B is a hydrophobic group that provides a chain carbon of at least 4 carbon atoms between the interconnecting L bonds) or a salt or chelator thereof, with the proviso that when Ch is 2,5-biscarboxymethyl-2,5-diazahex-1,6-diyl, the polychelant is metalated with lanthanide or manganese ions or B provides a carbon chain of at least 10 carbon atoms between the interconnecting L bonds, and their salts and chelates. The paramagnetic polychelates of the polychelants of the invention have Ri relaxations remarkably high

Description

JEttBA DESCRIPCl? W DH IA INVEHd? M This invention relates to polycarboxylic compounds and metal salts and complexes thereof, particularly polymetallated complexes useful as contrast agents for diagnostic imaging procedures, in particular magnetic resonance imaging (MRI). In medical imaging modalities such as magnetic resonance imaging, it has become an accepted practice to use contrast agents, ie, materials which improve contrast between tissues or organs or between diseased and healthy tissue in the images that are generated. In MRI, contrast agents generally achieve their contrast enhancing effect by modifying the relaxation times characteristic of image-forming nuclei (usually water protons) in the regions of the body in which they are distributed. Commercially available contrast agents which achieve a contrast enhancement in this way include gadolinium chelates REP: 26247 GdDTPA, GdDTPA-BMA and GdhP-D03A which are available from Schering, Nycomed Imagin and Squibb under the trademarks AGNEVISTMR, OMNISCAN "1 * and PROHANCE" 1 *, respectively. MAGNEVIST-, OMNISCA * 01 and PROHANCE "1 * are all ECF agents, ie, after injection into the vasculature and are distributed in the extracellular fluid (ECF) .Several propositions have been made in the patent literature and for accumulation in blood, compounds which, after injection into the vasculature, have a prolonged residence time in the blood spleens before they are generally eliminated via the liver or kidneys. proposed blood include polychelants (chelating agents capable of being metalated by a plurality of ions) metalated by transition metal ions or paramagnetic lanthanides see, for example WO90 / 12050 (Sieving), WO93 / 06868 (atson), O93 / 06148 (Unger), EP-A-512661 (Schering), etc. The use of polychelants has the advantage that a plurality of contrast-generating metal ions can be supplied simultaneously. e, so a concentrated contrast enhancement effect is provided.

Various polychelating structures have been proposed from simple dimeric or macrocyclic chelators (see for example EP-A-485045 and WO95 / 09848) to star discharge dendrimers carrying chelating groups at the dendrimer terminal (see, for example, WO93 / 06868 ). Linear polychelators have also been proposed in which the chelating group is attached to the polymer backbone (see EP-A-512661 and O90 / 12050). Other linear polychelators in which chelating groups are incorporated into the polymer backbone have also been proposed (see O94 / 08629 and WO93 / 06148). In the latter case, the polymers contain repeated units of chelants: binding polymer and the use of hydrophilic linking groups such as polyoxyalkylene or polyazaalkylene chains have been recommended, for example, by WO93 / 06148 and WO94 / 08629. In addition to serving to supply a plurality of diagnostically effective metal ions simultaneously, the macromolecular polychelants have the additional advantage, relative to simple monokelates such as GdDTPA, that their anisotropic rotational correlation time is longer, resulting in a relaxation increased and therefore an increased efficacy in contrast enhancement by MR.

Polymeric polychelators that incorporate alternating chelating and hydrophobic linker portions have also been proposed. Thus, for example GB-A-1304063 (Stauffer) propose certain EDTA-derived polymers for use as chelating agents, coagulants, flame retardants, detergent accumulators, etc. Among the polymers derived from EDTA proposed by Stauffer are polymers having hydrophobic linking groups such as hexamethylene, phenylene and 2,2-bis (1,4-phenylene) -propane. Unger in WO93 / 06148 further proposes various polymeric polychelators for use as contrast agents for RMI which are based on alternating chelating portions and hydrophilic linking portions such as polyoxyalkylene groups. Although Unger does not provide examples of compounds with hydrophobic linking groups, it makes the suggestion that the monomeric precursor for the hydrophilic linker (the compound of formula I) can be substituted by other monomers included in a list and included in its list as a small number of monomers that can give rise to hydrophobic linking groups, for example, 1,4-diaminobutane, 1,4-diaminocyclohexane and 1,4-phenylenediamine. Neither Stauffer nor Unger, however, adds any particular benefit to the use of hydrophobic linker groups and actually the main teaching of Unger towards the use of hydrophilic binders.

The present invention is based on the fact that substantially increased relaxations are obtained by using polymeric polycarboxes in which the linking groups that bind to the chelating portions are relatively large hydrophobic groups. Therefore, when considered from one aspect, the invention provides a polymeric polychelant having polymeric repeat units of formula I - [L-Ch-L-B] - (I) (wherein Ch is a polyvalent or polyvalent chelating moiety, L is an amide or ester bond, and B is a hydrophobic linking group that provides a carbon chain of 6 to 30 carbon atoms between the interconnecting L groups) or a salt or chelate thereof, with the proviso that when Ch is 2,5-biscarboxymethyl-2,5-diazahex-1,6-diyl, the polychelant is metalated with lanthanide or manganese ions or B provides a carbon chain of At least 10 carbon atoms between the L groups that interconnect. Preferably, the linking group contains 6 or fewer carbons, the chelating portion is a polyprotic species having at least 3 labile hydrogens.

The high relaxation obtained surprisingly by the metalated polychelants of the invention is capable of being demonstrated by a comparison of relaxations (at 40 ° C, 20 MHz) for the homologous series: [NOCOCH2N (CH2COO-) CH2CH2N (CH2C0O ") CH2CH2N (CH2COO)" CH2C0NH (CH2) y)] x Gd3 + Relaxation results for such polymers, where Y is from 4 to 12, are set forth in Table I below.

Table 1 The increase in relaxation to magnetic field resistance relevant to MRI (for example 0.24 Tesla or higher) with increasing numbers of melenes in the alkylene chain bridging in such polymeric polychelants is doubly unexpected. First, the mode of attachment of the chelator to the linker within the polymer structure is identical in each case and consequently the flexibility of the chelating portions at their junction points within the polymer structure, and consequently their movements, would be expected. - Anisotropic rotations should be very similar. Due to the anisotropic rotational movement of the chelate complex portions which dominate the correlation time to magnetic field forces relevant to MRI, one would expect very similar relaxations (See, for example Woessner in J. Chem. Phys. 2: 1 -4 {1962) and Koenig et al in Progress in NMR Spectroscopy 22: 487-567 (1992). Second, an increase in the number of methylene groups within the linker portion would result in more flexibility in the polymer chain. This would be expected to cause an increase in the anisotropic rotational correlation time and as a result decrease the relaxation (see Woessner, Supra). Therefore, since it would be expected that with homologous series the relaxations remain almost constant or decrease as the number of methylene groups in the binder increases, the fact that the relaxations increase markedly as the number of methylenes increases is completely unexpected. The hydrophobic binder B in the compounds of the invention may have a linear, branched, cyclic or partially cyclic carbon skeleton (for example -alkylene-phenylene-alkylene-) which may be completely or partially unsaturated and optionally may be substituted by hydrophobic groups such as-for example, iodine and fluorine atoms. However, preferably, the hydrophobic portion B will be linear, optionally partially unsaturated and optionally interrupted by one or more C5.7 homocyclic groups, for example, cyclohexylene or phenylene. Preferably, B contains up to 30, especially 8 to 30, and particularly 10 to 20 carbons. The carbon chain in the groups L which is provided by the hydrophobic group B is preferably 6 to 30 carbons in length and any side chain is preferably up to 6 atoms in length. Thus, B can be, for example, in the form of a chain consisting of the following units: m units of CH2, n units of CHR q units of C6H4, r units of CSH10, and p units of -CH = CH- where R is C1-6alkyl, and m, n, p, qyr are independently zero or positive integers, the sum of m + n + 2q + 2r + 2p is from 6 to 30, preferably from 6 to 25 and especially from 8 to 20. , where n, q and r are preferably 0, 1, or 2, the product q and preferably is zero and p is preferably 0, 1, 2 or 3. Thus, they can be, for example, a group of formula II - - (CHR) nl (CH2) rl (CH = CH) p (CH2) m2 (CHR) n2- (II) where R is as defined in the foregoing and ni, n2, ml, m2 and p are zero or positive integers, the sum of nl + n2 + ml + m2 + 2p is from 6 to 30, preferably from 6 to 25 , and especially preferably from 8 to 20. Particular examples of hydrophobic linker groups B include: (CH2) S, (CH2) 7, (CH2) 8, (CH2) 9, (CH2) 10, (CH2) X1 , (CH2) 1, (CH2) 13, (CH2) 14, (CH2) 1S, (CH2) 1S, (CH2) 17, (CH2) lß, (CH2) 19, (CH2) 20, 1,4-cyclohexylene. The linker group B is preferably a linear alkylene chain having at least 7 carbon atoms or a linear alkenylene chain.

The L bonds which couple the hydrophilic groups B to the Ch chelating portions are ester or amide groups, preferably carbon oxyacids, sulfur or phosphorus, that is, they provide a CN, SN, PN, CO, SO or PO within the main structure of the polymer. The amide nitrogens in such groups may be substituted or alternatively and preferred in themselves substituted by hydrophilic groups or, more preferably by hydrophobic groups such as C1-6 alkyl groups. The oxygen ester and nitrogen amide may be attached to the chelating moiety; however, it will generally be preferred that the hydrophobic binder B be attached to a terminal carbon since this configuration can be easily obtained by condensation of a bifunctional linear compound with an optionally activated oxyacid group containing a chelator, e.g. an α, β-alkylene diamine with DTPA-bisanhydride. Examples of bonds of this type include -CO-0, -O-CO-, -CO-NH-, -CO-NR-, -NH-CO-, -NR-CO-, -P03H-0-. The chelating portion in the polymeric polychelators of the invention can be any chelating group capable of stably binding paramagnetic metal ions. Many suitable chelating species have been described in the patent and scientific literature, especially that relating to metal-chelated MRI contrast agents and the reader is referred to the patent publications of Nycomed Imaging, Nycomed Salutar, Sterling Winthrop, Schering , Squibb, Malinckrodt, Braceo and Guerbet. Particularly preferably, the chelating portion will be the residue of a linear, branched or macrocyclic poly-N- (oxyacid-methyapolyzazacane, such as EDTA, DTPA, DOTA, D03A, DOXA and TTHA.) Thus, the chelating moiety can, for example, be of formula III (X-CHRÍCHR UX (III) wherein Rx is hydrogen or alkyl optionally substituted with hydroxy or alkoxy, or a bond or an alkylene group attached to an L bond, or two RL groups together may represent a C4-6 alkylene bridge optionally substituted with aza or oxa; k is 1, 2, 3, 4, 5 or 6, preferably 2 or 3; each X is independently O or NR2, or a bond to the nitrogen of an L-amide bond, at least two X groups are NR2; each R2 independently is a hydrogen atom or an alkyl group optionally substituted by hydroxy, alkoxy or COZ, POZ2, S02Z, CON (R3) 2, or linked to an L bond or two R2 groups together represent a CHRÍCHRÍ group, at least two R2 groups represent alkyl groups substituted with COZ, POZ2, S02Z or CON (R3) 2; Z is a group OR3 or N (R3) 2; and R3 is hydrogen or optionally hydroxylated alkyl; with two of X, Rt and R2 providing bonds to the L-bonds. As mentioned above, such chelating portions are well known from the literature in relation to contrast agents for MRI of metal chelate. The Ch portions preferred as chelators are groups having the structures wherein the carbon skeletons are unsubstituted, two nitrogens have methylene groups attached to L-bonds and the remaining nitrogens have oxyacid-methyl groups or amides or esters thereof, preferably carboxymethyl or phosphonomethyl groups. The compounds of the invention are polymeric containing repeating units of polymer [L-Ch-L-B]. The total molecular weight of the polymer is conveniently in the range of 103 to 106 D, preferably from 5 to 200 kD, and especially from 14 to 80 kD. The polymers of the invention may include additional structural units in addition to repeating units [L-Ch-LB], and in particular the inclusion of a relatively low proportion of hydrophilic polymer segments, either as bound groups or as components of the main structure of the polymer, which may be advantageous, for example, in terms of prolongation of residence times of accumulated blood. Groups which can be attached or incorporated in this manner include, in particular, polyazaalkylene and more particularly polyoxyalkylene chains, in particular polyethyleneoxy or polypropyleneoxy groups, for example PEG (polyethylene glycol) groups. Such groups can be attached or incorporated within the main structure of the polymer and advantageously constitute up to about 15% by weight of the polymer. The incorporation of such hydrophilic chains can be carried out by conventional techniques, see, for example, W093 / 06148 (Unger) and W094 / 08629. Such hydrophilic chains act as biodistribution modifiers for the polymeric compounds. Other biodistribution modifiers may also be conjugated to the polymeric compounds in order to target the polymer for body tissues or particular sites after administration. In this regard, particular mention can be made of macromolecules, biomolecules and macrostructures. Examples of macromolecules, biomolecules and macrostructures to which the polymeric chelator can be conjugated include polymers (such as polylysine), polysaccharides, protein, antibodies or fragments thereof (especially monoclonal antibodies or fragments such as Fab fragments), glycoproteins, proteoglycans , -peptides, hormones, steroids, cell adhesion molecules, etc. In this way, for example, polymeric polychelators targeting tumors can be produced. The conjugation of the polychelants of the invention to biodistribution modifying agents can be carried out by conventional methods as has been widely described in the literature of MRI contrast agents, for example, in WO90 / 12050, EP-A-512661, WO95 / 09848, etc. The polymeric polychelators of the invention are proposed primarily for use as MR contrast agents for which use will be metalated by paramagnetic metal ions or by ions in polyatomic groups (for example polyoxyanion and its sulfur analogues), for example transition metal ions or of lanthanide metals. The polychelating compounds of the invention can however be used to transport other metal ions for use in different modalities of diagnostic image information or in therapy. Especially preferred are metal polychelates with atomic numbers 20 to 32, 42 to 44, 49 and 57 to 83, especially Gd, Dy, Mn and Yb. For use as diagnostic MR contrast agents, the chelated metal species are particularly suitable as a transition metal or a latinate, preferably having an atomic number of 21 to 29, -42, 44 or 57 to 71. The chelates Metals in which the metal species are Eu, Gd, Dy, Ho, Cr, Mn or Fe are especially preferred, and multiple chelates metalated with Cd3 +, Mn2 + or Dy3 + are particularly preferred. For use as contrast agents in MRI, paramagnetic metallic species are conveniently non-radioactive since radioactivity is a characteristic which is neither required nor desirable for diagnostic MR contrast agents. For use as X-ray or ultrasound contrast agents, the chelated metal species are preferably heavy metal species, for example, non-radioactive metal with an atomic number greater than 37, preferably greater than 50, for example, Dy3. *.

For use in scintigraphy, or adiotherapy, chelated metal species must of course be radioactive and any isotope of radioactive metal forming conventional complexes such as 99Tc, 67Ga, or 111In, for example, can be used. For radiotherapy, the chelating agent may be in the form of a metal chelate with, for example, 1S3Sm, d7Cu or 90Y. For use in heavy metal detoxication, the polychelant is desirably in salt form with a physiologically acceptable counter ion, for example, sodium,. calcium, ammonium, zinc or meglumine, for example, as the sodium salt of a polychalcium chelate complex. When the polychelates are ionic, for example when the deprotonated chelating portion has a negative charge greater than that required to balance the positive charge of the complex metal ions, the compounds can be presented in the form of salts. In such cases, the counterions will preferably be physiologically tolerable organic or inorganic ions, such as ammonium, substituted ammonium, alkali metal or metalalcalinothermal. In this regard, meglumine salts are particularly preferred. The polymeric compounds of the invention can be prepared and metallated by conventional polymerization and metallation techniques and these form a further aspect of the invention. Viewed from this aspect, the invention provides a process for the preparation of the compounds of the invention, the compound comprises, at least one of the following steps: (a) copolymerizing a difunctional compound of formula IV with a difunctional compound of formula V Y2-Ch-Y2 (V) wherein B and Ch are as defined in the above and Yx and Y2 are interreactive groups to produce an amide or an ester linkage; (b) metalar or transmetal polymeric polychelant having repeating units of polymer of formula I as defined above, (c) conjugating a bioobjective group to a polymeric polychelant having repeating units of polymer of formula I as defined in previous; (d) copolymerizing difunctional compounds of formula IV and V together with an additional monomer of formula VI in which Y? is as defined in the foregoing and Hp is a linking group, for example, polyoxyalkylene species (such as the group of formula (CH 2) 2 (OCH 2 CH 2) t), preferably one having a molecular weight of 400 to 5000 In the polymerization reactions of the stages (a) and (d) above, Yx is preferably a hydroxyl, or more preferably a primary or secondary amine group, and Y2 is preferably optionally activated oxyacid, such as, for example, an acid chloride or more preferably an anhydrous group of acid. The bifunctional reagents of formulas IV and VI are known or can be prepared using conventional chemical techniques. The larger hydrophobic components for the compounds of formula IV can be accumulated from smaller components. The molecular weight of the polymer product can be regulated by appropriate selection of the polymerization reaction parameters (i.e., temperature, solvent concentration, monomer ratio, catalyst bases, etc.). Polyethylene methylation can be carried out using conventional techniques, either by direct metalation or by transmetallation, for example, by reacting the polychelant in solution with the soluble salt of the metal, for example, a chloride salt or with an oxide of metal. As indicated in the above, polychelants of the invention can be used as agents for diagnostic imaging or therapy. Therefore, viewed from a further aspect, the present invention provides a diagnostic or therapeutic agent comprising a polymeric polychelate according to the invention, together with at least one pharmaceutical or veterinary carrier or excipient. View from an additional aspect, the invention provides a detoxification agent comprising a polychelant according to the invention in the form of a weak complex or salt with a physiologically acceptable counter ion, together with at least one pharmaceutical or veterinary carrier or excipient. Viewed from a further aspect, the invention provides the method for generating improved images of the human or non-human body, preferably mammalian, animal, which method comprises administering to the body a diagnostically effective amount of a polychelator according to the invention polymetallated with a diagnostically effective metal, and generate an image of at least part of the body to which the metalated polychelant is distributed. Seen from another aspect, the present invention also provides a method of radiotherapy practiced in the body of the human or non-human animal, preferably a mammal, which method comprises administering to the body an effective amount of a chelate or a radioactive metal species. with a polychelant according to the invention. Seen from another aspect, the present invention provides a heavy metal detoxification method practiced in the body of the human or non-human animal, preferably a mammal, which method comprises administering to the body an effective amount of a polychelant in accordance with invention or a physiologically tolerable salt or a weak complex thereof. Seen from a further aspect, the present invention provides the use of a polymeric compound according to the invention for the manufacture of diagnostic or therapeutic agents.

The diagnostic and therapeutic agents of the present invention can be formulated in conjunction with conventional pharmaceutical or veterinary formulation aids, for example, stabilizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents, chelators, calcium salts or complexes, etc., and may be in a form suitable for parenteral or enteral administration, for example, for administration for injection or infusion or directly in a body cavity having an external vent. Therefore, the agent of the present invention can be in a conventional pharmaceutical administration form such as a tablet, capsule, powder, solution, suspension, dispersion, syrup, suppository, etc., however, solutions, suspensions and Dispersions in physiologically acceptable carrier media, for example water for injections, are generally preferred. The compounds according to the invention can therefore be formulated for administration using physiologically acceptable carriers or excipients in a manner completely within the skill of the art. For example, the compounds, optionally with the addition of pharmaceutically acceptable excipients, can be suspended or dissolved in an aqueous medium, and the resulting solution or suspension can be sterilized.

If the compounds are to be formulated in a suspension form, for example, in water or physiological saline for oral administration, a small amount of soluble chelates can be administered with one or more of the active ingredients traditionally present in oral solutions and / or surfactants and / or aromatics to flavor. For MRI and X-ray imaging, the most preferred way to administer the metalated polychelators of the invention will be parenteral, for example, intravenous administration. Parenterally administrable forms, for example intravenous solutions, must be sterile and free from physiologically unacceptable agents, and must have low osmolarity to minimize irritation and other adverse effects when administered, and therefore the contrast medium should preferably be Isotonic or slightly hypertonic. Suitable carriers include aqueous vehicles commonly used to administer parenteral solutions such as sodium chloride injection, injection of Ringer's solution, excretion injection, injection of dextrose and sodium chloride, injection of lactated Ringer's solution and other solutions such as those described in Remmington Pharmaceutical Sciences, 15th edition, Easton: Mack Publishing Company, pages 1405-1412 and 1461-1487 (1975) and The National Formulary XIV, 14th edition, Washington, American Pharmaceutical Association (1975). The solutions may contain preservatives or preservatives, antimicrobial agents, buffers and antioxidants conventionally used for parenteral solutions, as well as excipients and other additives which are compatible with polymeric agents and which do not interfere with the manufacture, storage or use of the products. . When the diagnostic or therapeutic agent comprises a chelate or salt of a toxic metal species, eg, a heavy metal ion, it may be desirable to include within the formulation a slight excess of the chelating agent, for example, as described by Schering in DE-A-3640708, or more preferably a slight excess of the calcium salt of such a chelating agent. For diagnostic examination by MR, the diagnostic agent of the present invention, whether in the form of solution, suspension or dispersion, will generally contain the metal chelate at a concentration in the range of 1 micromole to 1.5 mol per liter, preferably 0.1 to 700 mM. However, the diagnostic agent can be delivered in a more concentrated form for dilution prior to administration. The diagnostic agent of the invention can be conventionally administered in amounts from 10"3 to 3 mmol of the metal species per kilogram of body weight, for example, from about 0.1 mmol of lanthanide (for example Dy or Gd) / kg of body weight. For X-ray examination, the dose of the contrast agent will generally be higher and for the scintigraphic examination the dose will generally be lower than for the MR examination. For radiotherapy and detoxification, conventional dosages can be used. The present invention will now be illustrated in a manner, in addition to the following examples.

EXAMPLE l 1.6-Hexanediamine Polymer: DTPA To a solution of 2.97 g (25.5 mmol) of 1,6-hexanediamine in 45.1 ml of dimethyl sulfoxide are added 11.08 ml (79.5 mmol) of triethylamine and 9.45 g (31.8 mmol) of diethylenetriaminepentaacetic dianhydride with vigorous stirring. The resulting reaction mixture is stirred at room temperature for 28 hours to provide a homogeneous solution, after which it is diluted to about 1% solids content with water and subjected to diafiltration for 5 replacements using a molecular weight threshold of 10,000, with a spirally wound polysulfone diafiltration membrane. The resulting aqueous retentate is then lyophilized to provide a hygroscopic white solid. Yield: 7.6 g.

EXAMPLE 2 omplex d = Qd (III) d = polymer e 1.6-haxanodiamina: DTPA .0 g of the polymer of Example 1 are dissolved in 600 ml of deionized water and stirred at moderate speed as it is slowly treated with a 5% aqueous solution of gadolinium chloride hexahydrate (III). The addition is continued until a small test sample, dripped on a PAR test reagent, causes a color change from light yellow to strong yellow. The PAR test reagent has been previously prepared by sonicating a mixture of 40 ml of deionized water, 20 ml of trace metal-grade ammonium hydroxide and 0.005 g of 4- (2-pyridazo) resorcinol for 1 minute. After sonication, it is treated with 5.7 ml of trace-grade metal acetic acid, allowed to cool to room temperature and diluted with 100.0 ml with additional deionized water. Upon observing the color change in the PAR reagent, the polymer complex is subjected to diafiltration as in Example 1 for 6 replacements, after which the pH 6.5 is adjusted with 3.0 M NaOH. The product is subsequently lyophilized to produce a fluffy white solid. Yield: 6.6 g. Average molecular weight: 28100 Average molecular weight number: 20400 Polymer dispersion: 1.38 Gadolinium content: 21.75 weight percent of bound gadolinium and 0.009 weight percent of free gadolinium.

EXAMPLE 3 1.8-octane diamine polymer: DTPA The title compound is produced analogously to Example 1 using 1,8-octanediamine.

RJEMP O 4 C -mple of Gd (III) of l.fi-optediamine polymer: DTPA The title compound is produced analogously to Example 4 using the polymer of Example 3. Average molecular weight: 16200 Average number of molecular weight: 10100 Dispersiveness of the polymer: 1.6. Gadolinium content: 19.95 weight percent of gadolinium bound.

EXAMPLE 5 1.10-Decaniamine Polymer: DTPA To a solution of 1.78 g (10.3 mmoles) of 1,10-diaminodecane in 45.4 ml of dimethylsulfonic add 4.44 ml (31.8 mmoles) of triethylamine and 3.78 g (10.6 mmoles) of diethylenetriaminepentaacetic dianhydride with vigorous stirring. The resulting reaction mixture is stirred at room temperature for 17 hours to provide a homogeneous solution, after which it is diluted to about 1% solids with water and subjected to diafiltration for 8 refills using a coiled polysulfone diafiltration membrane spiral, with nominal 10,000 molecular weight cut. The resulting aqueous retentate is subsequently lyophilized, which provides a hygroscopic white solid. Yield: 3.1 g EXAMPLE 6 Cope or ds Gd (III) of polymer of 1.10-. Dgcaniamine; DTPA 2.2 g of the polymer of Example 5 are dissolved in 220 ml of deionized water and stirred at moderate speed and at the same time treated slowly with a 5% aqueous solution of gadolinium chloride hexahydrate (III). The addition is continued until a small test sample, dripped on a PAR test reagent, causes a color change from light yellow to strong yellow. The PAR test reagent has been prepared as previously described in Example 2. By observing the color change in the PAR reagent, the polymer complex is diafiltered as in Example 5 through 6 additional replacements, after which the pH is adjusted to 6.5 with 3.0 M NaOH. The product is then lyophilized to produce a fluffy white solid. Yield: 1.64 g. Average molecular weight: 10300 Average molecular weight number: 6800 Polymer dispersion: 1.52 Gadolinium content: 19.92 weight percent of bound gadolinium and less than 0.001 weight percent of free gadolinium.

EXAMPLE 7 Polymer 1.1 -dedecane diamine: DTPA The title product is prepared analogously to the compound of Example 1 using 1,12-dodecanediamine as the starting diamine.

EXAMPLE 8 Sd (III) polymer complex of 1.12- odecanodiamine, DTPA The Gd (III) complex of the polymer of Example 7 is prepared analogously to the Gd (III) complex of Example 2.

Average molecular weight: 15700 Average molecular weight number: 8700 Polymer dispersion: 1.8 Gadolinium content: 20.06 percent by weight.

EXAMPLE 9 The complex of Gd (III) of the polymer 1,6-hexanediamine: DTPA with molecular weights of 9 kD, 14 kD, 18 kD with GdTPA (Magnevist) is compared to determine its retention in blood, in rabbits. Each rabbit is injected with one of the contrast agents at a concentration of 0.1 mmol Gd per kg of body weight. Blood samples are taken at various points in time for each animal and the longitudinal relaxation rate (rt in mM "1s" 1) at a temperature of 40 ° C and a magnetic field strength of 0.47 teslas is measured. The results are set forth in Figure 1 herein. This ex vivo experiment correlates directly with the study of magnetic resonance imaging in vivo in Example 10 below demonstrating an improvement in magnetic resonance imaging as a function of time.

E EMPLO 10 The Gd (III) complexes of the polymer 1,6-hexanediamine: DTPA used in Example 9 are also used in an imaging study, again in rabbits. Each rabbit is injected with one of the contrast agents at a concentration of 0.1 mmol Gd per kg of body weight. Magnetic resonance imaging of the muscle and inferior vena cava is performed on each animal, at various points in time. The strength of the magnetic field used is 1.5 Tesla. The results of imaging are set forth in Figure 2 of the accompanying drawings.

EXAMPLE 11 1,4-Butanediamine polymer; DTPA The title compound is prepared analogously to the polymer described in Example 1, except that the diamine used is 1,4-butanediamine. Average molecular weight weight; 15,000 EXAMPLE 12 Coefficient of Gd (III) d = polymer of 1.4-hnf.anndiamina.DT A The gadolinium complex of the polymer of Example 11 is prepared and purified in a manner similar to that described in Example 2. Average molecular weight: 8000 Average number of molecular weight: 5700 Dispersivity of the polymer: 1.41 Content of gd: 26.2 % (in weigh).

EXAMPLE 13 1.5-pentanediamine polymer: DTPA The title compound is prepared analogously to the polymer described in Example 1, except that the diamine used is 1,5-pentanediamine. Average molecular weight: 12700 Average molecular weight number: 6900 Polymer dispersion: 2.31 EXAMPLE 14 Complex d = Gd (III) of polymer of 1,5-pentanediamine; DTPA The gadolinium complex of the polymer of Example 13 is prepared and purified in a manner similar to that described in Example 2. Average molecular weight: 8300 Average molecular weight number: 5600 Polymer dispersion: 1.48 Gd content: 25.6 % (in weigh) .

EXAMPLE 15 Polymer N.N '-dimethyl-1,6-hexanediamine: DTPA The compound of LLtU-? analogously to the polymer described in Example 1, except that the diamine used is N, N'-dimethyl-1,6-hexanediamine. Average molecular weight: 28,600 Average molecular weight number: 11,800 Polymer dispersion: 2.41 EXAMPLE 16 Gd (III) Polymer Complex N.N '-dimetd -1.6-hexanediamine: DTPA The gadolinium complex of the polymer of Example 15 is prepared and purified in a manner similar to that described in Example 2. Average molecular weight: 16,700 Average molecular weight number: 9200 Polymer dispersion: 1.81 Gd content: 26.2% (in weigh) .

EXAMPLE 17 Trans-1,2-diaminocyclohexane polymer: DTPA The tlüilü compound is prepared analogously to the polymer described in Example 1, except that the diamine used is trans-1,2-diaminocyclohexane. Average molecular weight: 8300 Average molecular weight number: 5900 Polymer dispersion: 1.40.

EXAMPLE Ifl Com o d = Gd U l d = trana-1.2-diaminocycle exano The gadolinium complex of the polymer of Example 17 is prepared and purified in a manner similar to that described in Example 2. Average molecular weight: 5400 Average molecular weight number: 4000 Polymer dispersion: 1.37. Gd content: 24.94% (by weight).

EXAMPLE 19 Polymer N.N '-diethyl-2-buten-1,4-diamine: DTPA The title compound is prepared analogously to the polymer described in Example 1, except that the diamine used is N, N'-diethyl-2-buten-1,4-diamine. Average molecular weight: 16,100 Average molecular weight number: 6600 Dispersive polymer: 2.45.

EXAMPLE 20 Gd (III) complex of N. N '-diethyl-2-buten-1,4-diamine The gadolinium complex of the polymer of Example 19 is prepared and purified in a manner similar to that described in Example 2. Average molecular weight: 16,100 Average molecular weight number: 11,400 Polymer dispersion: 1.41 Gd content; 21.16% (by weight).

The longitudinal proton relaxation for the compounds according to the invention (^ nM '-' S "1) was measured at a proton Larmor frequency of 20 MHz and a temperature of 40 ° C in aqueous solution. Table II below.

Table II EXAMPLE NO. RELAXATION (R nM ^ s "1 2 9.5 4 12.0 6 16.5 8 20.7 12 7.98 14 8.49 16 9.5 18 11.7 20 13.7 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (21)

REIVINDIgAgTQNES

1. A polymeric polychelant having repeating units of polymer of formula I - [L-Ch-L-B] - (I) (wherein Ch is a polyvalent or polyvalent chelating moiety; L is an amide or ester bond; B is a hydrophobic group that provides a carbon chain of 6 to 30"carbon atoms between the interconnecting L bonds) ionized by ions paramagnetic lanthanide or manganese, or a salt thereof.

2. The polymeric compound according to claim 1, polymetallated by paramagnetic metal ions.

3. The polymeric compound according to claim 1, polymetallated by gadolinium ions or dysprosium.

4. The polymeric compound according to any of claims 1 to 3, characterized in that B contains up to 50 carbon atoms.

5. The polymeric compound according to any of claims 1 to 4, characterized in that B provides a link chain consisting of the following units: m CH2 units, n CHR units, q C6H4 units, r CSH10 units and p CH = CH units, where R is alkyl of m, n, p, q and r are independently zero or positive integers, and the sum of n + m + 2q + 2r + 2p does not exceed 30.

6. The polymeric compound according to any of the preceding claims, characterized in that B is a group of the formula (CHR) nl (CH2) ml (CH = CH) p (CH,) ^ (CHR) n2 wherein R is C1-6 alkyl, ni, n2, ml, m2 and p are zero or positive integers, and the sum of nl + ml + n2 + m2 + 2p does not exceed 30.

7. The polymeric compound according to any of the preceding claims, characterized in that B is a linear alkylene group having at least 7 carbon atoms or a linear alkenylene group.

8. The polymeric compound according to any of the preceding claims, characterized in that B is a linear polymethylene group of

9. The polymeric compound according to any of the preceding claims, characterized in that L is a group -CO-O-, -CO-NH- or -CONR-, wherein R is C 1 alkyl.

10. The polymeric compound according to any of the preceding claims, characterized in that Ch is the residue of a linear, branched or cyclic poly-N- (oxyacid-methyl) -polyazaalkane.

11. The polymeric compound according to claim 10, characterized in that Ch has one of the following structures: wherein the main carbon structure is unsubstituted, 2 nitrogens have methylene groups attached to L-groups, and the remaining nitrogens have oxyacid-methyl groups or amides or esters thereof.

12. The polymeric compound according to claim 11, characterized in that Ch is 2,5,8-triaza-2,5, 8-triscarboxymethyl-nonan-l, 9-diyl.

13. The polymeric compound according to any of the preceding claims, characterized in that it has a molecular weight from 5 kD to 1000 kD.

14. The polymeric compound according to any of the preceding claims, characterized in that it has a molecular weight from 14 kD to 50 kD.

15. The polymeric compound according to any of the preceding claims, characterized in that a biodistribution modifier portion is incorporated or attached to the polymeric backbone.

16. A therapeutic or diagnostic composition characterized in that it comprises a polymeric compound according to any of the preceding claims together with a pharmaceutical or veterinary carrier or excipient.

17. A process for the preparation of a compound according to claim 1, the process is characterized in that it comprises at least one of the following steps (a) copolymerizing a difunctional compound of formula IV Yx-B-Y! (IV) with a difunctional compound of formula V Y2-Ch-Y2 (V) wherein B and Ch are as defined in claim 1 and Yx and Y2 are interreactive groups to produce an amide or an ester linkage; (b) metalar or transmetalar polymeric polychelant - having repeating units of polymer of formula I; (c) conjugating a bioobjective group to a polymeric polychelant having repeating units of polymer of formula I; Y (d) copolymerizing difunctional compounds of formula IV and V together with an additional monomer of formula VI in which Yx is as defined in the above and Hp is a linking group.

18. A method for generating improved images of an animal body, human or non-human, method which is characterized in that it comprises administering to the body a diagnostically effective amount of a polychelant according to claim 1 polimetalated with a diagnostically effective metal, and generating an image of at least part of the body in which the metalated polychelant is distributed.

19. A radiotherapy method practiced in an animal body, human or non-human, method which is characterized in that it comprises administering to the body an effective amount of a chelate of a radioactive metal species with a polychelant as defined in accordance with claim 1 .

20. A heavy metal detoxification method practiced in a human or non-human animal body, which method comprises administering to the body an effective amount of a polychelant according to claim 1 or a physiologically tolerable weak salt or complex thereof.

21. The use of a polymeric compound according to claim 1, for the manufacture of diagnostic or therapeutic agents.