MXPA99009190A - Chelating agents - Google Patents

Abstract

The invention provides a complexant compound of formula (I):R3S(CR12)nN(R2)i(CR12)nX(CR12)nN(R2)i(CR12)nSR3, (wherein each n, which may be the same or different, is an integer 2, 3 or 4 (preferably 2);each i, which may be the same or different, represents 0 or 1;each R3, which may be the same or different, is H or a thiol protecting group, preferably a protecting group;X is O, S, N, NR4 or a substituted phosphorus (e.g. oxo substituted phosphorus), preferably S or N;each R4, which may be the same or different, is hydrogen or an optionally substituted organic group;each R2, which may be the same or different, is hydrogen or an optionally substituted organic group;each R1, which may be the same or different, is hydrogen or an optionally substituted organic group, or a moiety CR12 may represent a carbonyl group or two, three or four R1S on two different carbons together with those carbons and any intervening atoms may represent an optionally substituted saturated or unsaturated homocyclic or heterocyclic ring;and preferably, at least one CR12 moiety is other than CH2 or CH(CH3)) or a salt or complex thereof, wherein optionally at least one of the R1, R2, R3 and R4 moieties is coupled directly or indirectly to a vector moiety.

Description

AGENTS QU? LANTES FIELD OF THE INVENTION This invention relates to complex complexing compounds and to metal atoms thereof and to their use in prophylactic, therapeutic and diagnostic compositions, in particular to the use of such complex formers with metal atoms with radionuclides as a of diagnostic images and therapeutic agents.

BACKGROUND OF THE INVENTION Radiopharmaceuticals, the class of drug compounds containing radionuclides, are used for the diagnosis and treatment of various disease states, in particular, certain cancers.

The radionuclide in such radiopharmaceuticals can be a metal (for example a transition metal or a lanthanide) or a non-metal (for example a radionuclide of hydrogen or iodine).

When the radionuclide is a metal, it is conventionally administered as a complex (usually a chelate complex) of a mono ion or REF. 31521 polyatomic of or containing the metal, with an agent ± ormador of compiejo. The present invention relates in particular to complex metal-forming radionuclides and complexing agents, which may be with metal atoms with metal ion radionuclides.

In the use of complex metal-forming radiopharmaceuticals, the diagnostic or therapeutic properties are selected by the appropriate selection of the metal radionuclide (for example by virtue of its disintegrated or half-life model) while the properties of biodevelopment and bioelimination they are selected by the appropriate selection of the complex formers and, if desired, by a portion of the vector directly or indirectly coupled to the complex formers such as to cause the complex-forming radionuclide to be targeted to a site in the body or a particular type of tissue, for example, cancerous tissue.

Examples of complex formers that have been proposed for use with metal radionuclides in therapeutic or diagnostic compositions include, the terpyridine chelators described in WO-A-92/08494 and WO-A-93 / 2I 957 and the chelators BAT described by Ohmomo et al. in J. Med. Chem. 35_: 157-162 (1992) and by Kung et al. in J. Nucí. Med. 25: 326-332 (1984 ~).

Indeed, there is a continuing need for complexators who are able to adequately form metal therapeutic therapeutic radionuclides and which may also preferably be coupled to the effective vector portions so as to be the target of the forming radionuclides. of complexes a desired target site within the patient's body.

In particular, there is a continuing need for complex formers that can be used either diagnostically effective mechane radionuclide and therapeutically effective metal radionuclides. In this way a diseased site can be represented and treated using diagnostic and therapeutic agents, which have substantially identical biodistributions, from the carrier portion of the metal: carrier bead, which determines that the biodistribution model of the complexes can be the same in both, the diagnostic agent and the therapeutic agent.

It has now been found that a new class of complex formers possess appropriate properties in this regard.

DESCRIPTION OF THE INVENTION The new complex formers refer to lsers of N2S2X complexes, since they contain an interrupted carbon chain, for the heteroatoms S, N, X, N and S (where X is a heteroatom of O, S, N or P). Within these heteroatoms there are carbon chains of 2, 3, or 4 atoms in length. Such complexing agents, and the salts and builders thereof, which include the complexing formers thereof, form an aspect of the invention.

Upon review of a further aspect of the invention, a complexing compound of formula I is provided 3S (CR1í!) NN. { R2) i (C12 nX (C nW (? 4)? ICR12 _, i3R3 (I) (where each n, which can be the same or different, is an integer of 2, 3 or 4 (preferably 2); i, which may be the same or different, represents 0 or 1, each R3, which may be the same or different, is H or a protective thiol group, preferably a protective group, X is O, S, N, NR4 or a substituted phosphorus (for example, substituted oxo phosphorus), preferably S o; = Each R4, which may be the same or different, is hydrogen or an optionally substituted organic group; each R2, which may be the same or Each one is hydrogen or an optionally substituted organic group: Each R1, which may be the same or different, is a hydrogen group or an optionally substituted organic group, or a portion "CRX2 may represent a carbonyl group or two, three or four R1s are two different carbons together with those carbons and any atom that intervenes, can represent a homoloyalic ring or octet sat urated or unsaturated, optionally substituted; and preferably, at least one portion CR12 is preferably CH2 or CH (CH3)) or a salt or complex former thereof, wherein optionally at least one portion of R, R, R and R is directly or indirectly pooled to a portion of the vector.

In reviewing a further aspect, the invention provides a pharmaceutical composition comprising an effective amount (for example an effective amount for increasing the image contract in imaging or in an amount sufficient to achieve a desired therapeutic effect) of a complex of an complex former optionally coupled to a vector, of formula I together with at least one pharmaceutically effective carrier or excipient.

While still reviewing a further aspect, the invention provides the use of a compiler of a compiler optionally arrayed to a vector of formula I for the preparation of a contrast medium for use in a diagnostic method that invents the administration of said agent. means of contrast to an animated subject and the generation of an image of at least a part of said subject.

Further reviewing a further aspect, the invention provides the use of a compiler of a complex former optionally pooled to a vector of formula I, for the preparation of a therapeutic agent, eg, a radiopharmaceutical, for example, for use in tumor therapy.

While still reviewing a further aspect, the invention provides a method for the generation of an animated image of a human or non-human animal subject (preferably a mammal or a bird) that involves the administration of a contrast agent to said subject, for example, in the vascular system or the gastrointestinal tract, and the generation of an image of at least a part of said subject to which said contrast agent has been distributed, for example by means of X-rays, MR, ultrasound, scintiphography, PET, SPECT, impedance electrical, light or magnetometric image-forming modalities, characterized in that, as said contrast agent, a complex of a complex former optionally coupled to a vector of formula I is used.

While still reviewing a further aspect, the invention provides a method of treating a human or non-human animal subject (preferably a mammal or a bird) that involves the administration of a contrast agent to said subject, for example, in the vascular system or the gastrointestinal tract, characterized in that, as said therapeutic agent, a complex of a complex former optionally coupled to a vector of formula I is used.

While still reviewing a further aspect, the present invention provides a process for the preparation of a complex of a complex former optionally coupled to a vector of formula I, said process comprising the metal atoms in a complex former optionally coupled to a vector of Formula I, with a diagnostically or therapeutically effective metal ion or a metal ion containing a complex.

The formation of metal atoms can be effected using conventional techniques, for example, by reacting the complex former or a salt thereof in a solution with a soluble salt of the desired metal.

Where, in the compounds of formula I, the groups R1 together with the atoms involved in a cyclic group, it is particularly preferred that these be a 5- to 8-membered ring containing 0, 1, 2 or 3-heteroatoms selected from N , S and 0. More especially, is it preferred that one such heteroatom be provided by an N (R2)? or group X and it is even more especially preferred that the R1 groups are from two adjacent carbons but at different sites of an N (R2) or group X. Preferably, the compound of formula I will contain zero, one or three such heterocycles, preferably unsaturated and especially preferable, aromatic heterocycles, which incorporate rings of nitrogens, oxygens or sulfurs, of N (R2) ions X. Particularly preferred the resulting heterocycle is a heterocycle Ni, N2, Oi, iOi or Si unsaturated, preferably a ring thiophene, pyrroiidine, piperidine, piperazine, rapholinoline, pyran, pyrrole, imidazaoi, pyrazine, pyrimidine, imidazolidine, imidazolidinone, furan or pyridine. Preferred are pyridine, thiophene and furan rings, especially pyridine.

It is also preferred that the two groups (CR12) n between ei N (R2) x and the X portions should be the groups (CH2) __ or (CR) (CH2) n- ?, where X is S and where the portions CR1 ^ they are attached to the nitrogens. It is further preferred that the groups (CR12) adjacent to a group (CR12) and which is part of a cyclic group itself should be part of a cyclic group c should be CH or CK¿ group.

It is even more preferred that the CR12 portions adjacent to the SR3 groups should be CH2 or CR52 groups (where each R5 is independently an alkyl group, preferably an alkyl group of 1 to 3 carbon atoms), especially preferable CH2 or C groups. CHj) __. Such - portions CR1. they are preferably CR52 groups where the adjacent group (CR12 n-? N (R2)? is not part of a cyclic group.

Where a CRX2 group is a carbonyl group, this is preferably a group N (R2); Where such a carbonyl group is present, it is preferred that the other "adjacent group CR12-ai group N (R2)" should contain an amine or carbonyl function, for example, such as a group CR12 is a group CH-CH_COOH or CH -CH2CH2NH2.

Any cyclic group consisting of two CR12 groups and intervening atoms can, as indicated above, be optionally substituted, for example by at least one "hydroxy group, oxo, halo, alkyl, aryl, amino, CNS, carboxyl c acyl, for example by a hydroxy-amino-n-nyl group.

The organic groups which are substituents in the compounds of the formula I, in general will be groups of 1 to 20 carbon atoms, preferably groups of 1 to 10 carbon atoms, which optionally contain one or more, for example, up to six. heteroatoms (for example, halo atoms, N, S, P and 0). The alkyl, alkenyl, alkynyl and acyl moieties (including alkylene portions, etc.) will preferably contain up to 6 carbon atoms. The aryl portions will preferably be phenyl groups or N, S or O heterocycles of 5 to 7 members. However, other hydrophilic substituents, such as polyalkylene oxides (ie, ((CH2) mO) p where m is 2 or 3 and p =! An integer from 2 to 500) may be present, if desired as modifiers of the biodistribution When two groups NR2? are present, it is preferred that at least one R 2 is an amine, carboxyl or sulfur group or substituted oxy-acid phosphate of 1 to 6 carbon atoms, for example CH 2 CH 2 NH 2 or, more preferably, CH 2 COOH.

Preferably, the compounds of formula I are of formula II R3-S-C% (CH2) 0.2 (CRl8.} N (Rr) _ . {CR1z) (CH2) ft_; (CRxa) X (CR1 ^ - < CHB > ß 2 < CR1a) N. { Rz > i < CR l (CHa) "_2CR% SR3 (XI) where each CR 2, which may be the same or different, is CH2, CH or C, in the latter case, it is linked to an adjacent group CR12 to the same heteroatom to form a saturated or unsaturated 5 or 6 member heteorcycle , optionally substituted, and each R2 when present is H or an alkyl group of 1 to ß functionalized carbon atoms (for example CH2COOH), preferably one of R2 is instead of H.

Particularly preferably, each n is 2, X is S or N and O, 1, or 2 fused pyridine groups are present in the compounds of the invention. Thus, in particular, preferred compounds include those of formulas III to VII: (wherein R5 is hydrogen or, optionally substituted alkyl, aryl, alkaryl or aralkyl, R4 is H, or, preferably, CH3, R6 is H or functionalized alkyl, preferably one is H and the other is CH2COOH, and X * is a bonded carbon to an aromatic ring, for example, a ring 2,5-thiophene, 2,6-pyridine, 2,5-furan or 2,6-pyrimidine, optionally substituted by a group R 5).

In direct bonding to a vector group it is preferably via a carbon structure of a portion (CRx2) not via a carbon ring of a cyclic group consisting of two groups (CR12) and a heteroatom intervening of N (R2) io X , particularly, preferably via a phenyl group attached to such ring of the atom.

The protective thiol group R can be any of the known protective thiol groups (see, for example, Greene, "Protective groups in organic synthesis", Wiley Interscience, 1981 and McOmie, "Protective groups in organic chemistry", Plenu, 1973). Examples of such groups include alkyl groups of 1 to β carbon atoms, optionally substituted, for example, methoxybenzyl groups (mBz).

The complex formers of the invention may be coupled to a vector, a material, which will affect the biodistribution of complex formers or their complexes, for example a target to their particular receptors, organs, tissues or body compartments. Such couplings may be direct or may involve a linker, a bifunctional compound that binds the complex formers and the vector. Examples of suitable vectors include proteins, antibodies, antibody fragments, oiigopeptides, hormones, polyalkylene oxides, and pharmaceuticals (See, for example, WO 92/08494).

The compounds of the invention can be prepared by routine organic synthesis and the chelating metal atom formation techniques. Illustrative synthetic schemes are shown below.

Scheme I. Synthesis of TMT-S2 pßtoxilbenzilo wtn € 3539: 1 Scheme 2, Synthesis of Precursors 3. 80% 4,. generated in situ Scheme 3. Synthesis of N2S2-pyridine Scheme 4. Synthesis of N2S2X 9? X = S -lftX ± -N 11: X = -S 1KX-N Scheme 5 .. Synthesis of N2S2X-amide The complexing compounds of formula I can be metal atom formers with metal ions or complex or therapeutically effective ion ions (for example metal oxide ions or metal sulfide (such as TcO or VO)). Generally speaking, the preferred metal ions will be radionuclides, paramagnetic ions, fluorescent ions, or heavy metal ions (for example, with an atomic number greater than 53) or pooled ions.

Examples of suitable metals include Ag, At, Au, Bi, Cu, Ga, Ho, In, Lu, Pb, Pd, Pm, Pr, Rb, Re, Rh, Se, Sr, Te, TI, Y, and Yb.

Preferred metal radionuclides include 90Y, "mTC, lxlIn, 47Sc, 67Ga, 51Cr, 177mSn, 67Cu, 167Tm, 97Ru, 186Re, 177Lu, 199Au, 203Pb and 141Ce.

~~ Furthermore, γ-emitting radionuclides, such as 99mTC, 11; LIn, 67Ga and 16Yb have been approved under investigation for diagnostic imaging, while "β-emitter complexes, such as 67Cu, 11: LAg , 186Re and 90Y are more promising for applications in tumor therapy.Also, the emitters? (Examples are 99Tc, 11: LIn, 67Ga, and 169Yb) but also, the β-eminosters, (such as 67Cu, 11: LAg, 186Re, and 90Y), as well as other radionuclides of interest (211At, 212Bi, 177Lu, 86Rb, 105Rh, 153Sm, 198Au, 149Pm, '85Sr, 142Pr, 214Pb, 109Pd7 186Ho, 208T1, and 4 Sc). with hard metal ions, such as In3 +, Ga3 +, - Yb3 + and Y3 +, will be stable.In addition, since it contains two or three sulfur atoms, they are soft metals (Ag +, Cu2 +, Tc03 +, and Re03 +), the complexes also they must be stable. ' Paramagnetic metal ions include transition metal ions and lanthanides (for example, metals having atomic numbers of 21-29, 42, 43, 44, or 57-71), in particular, ions of Cr, V, Mn, Faith, Co, Ni, Cu, La, Ce, "Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, ~ Ho, Er, Tn, Yb and Lu, especially Mn, Cr, Fe, Gd and Dy, more especially Gd. 7_ The fluorescent metal ions include lanthanides, in particular La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu. Eu is especially preferred.

Reporters containing heavy metals can include atoms of "Mo, Bi, Si, and W and in particular, polyatomic pooled ions (eg, Bi compounds and W and Mo oxides) as described in WO91 / 144460, W092 / 17215, WO96 / 40287 and W096 / 22914.

All publications referred to herein are incorporated in their entirety for reference.

The compounds of the present invention can be administered to patients for imaging, in amounts sufficient to provide the desired contrast with the particular imaging technique. The dosages in general will be from 0.001 to 5.0 mmoles of metal ion-forming chelate per kilogram of body weight of the patient, are effective to achieve adequate increases in contrast. For more MRI applications, the preferred dosages of the imaging metal ions will be in the range of 0.02 to 1.2 mmoles / kg of body weight, while for the dosages for X-ray applications, from 0.05 to 2.0 mmoles / kg are available. general effective to achieve X-ray attenuation. Preferred dosages for more X-ray applications are from 0.1 to 1.2 branches of the iantanide or the heavy metal compound / kg body weight. When the chelated species is a radionuclide, dosages of 0.01 to 100 mCi, preferably 0.1"to 50 mCi will normally be sufficient for 70 kg / body weight.

The dosage of the compounds of the invention for therapeutic use will depend on the conditions to be treated, but "in general, they will be in the order of 1 pmol / kg to 1 mmol / kg of body weight.

The compounds of the present invention will be formulated with conventional veterinary or pharmaceutical adjuvants, for example, "esters, fatty acid esters, gelling agents, stabilizers, antioxidants, osmosis adjusting agents, buffers, pH adjusting agents, etc.- and they can be in a form suitable for parenteral or enteral administration, for example, injection or infusion or administration directly into a body cavity having an internal exhaust duct, for example, the gastrointestinal tract, the bladder or the uterus. Thus, the "compounds of the present invention can be in conventional pharmaceutical administration forms, such as tablets, capsules, powders, solutions, suspensions, dispersions, syrups, suppositories, etc. However, solutions, suspensions and dispersions in a physiologically acceptable carrier medium, for example water, for injections, will generally be preferred.

The compounds according to the invention can therefore be formulated for administration using physiologically acceptable carriers or excipients in a complete manner within those skilled in the art. For example, the compounds, optionally with the addition of pharmaceutically acceptable excipients, can be suspended or dissolved in an aqueous medium, with the resulting solution or suspension being sterilized For the imaging of some portions of the body, the most preferred mode for administration of the contrast agents is parenteral, for example, intravenous administration. Parenterally administrable forms, eg, intravenous solutions, should be sterile and free from physiologically unacceptable agents, and should have low osmolarity to minimize irritation or other adverse effects on administration, and thus, the contrast medium should preferably be isotonic or slightly hypertonic. Suitable carriers include aqueous vehicles daily used for the administration of parenteral solutions, such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose Injection and Sodium Chloride, Lactated Ringer's Injection and other solutions such as " described in Remington 's Pharraaceuticai Sciences, 15th ed., Easton: Mack Pubiishing Co., pp. 1405-1412' and 1461-1487 (1975), and The National Formulary XIV, 14th ed. Washington: American Pharmaceutical Association (1975). The solutions may contain preservatives, antimicrobial agents, buffers, and antioxidants conventionally used for parenteral solutions, excipients and other additives which are compatible with the queiates and which will not interfere with the preparation, storage or use of the products.

The invention is further illustrated by the following non-limiting examples. The "numbering" of the compounds is as in the reaction schemes illustrated above.

Example 1 Preparation of 2: To a solution of 76 mg of NaH in 130 ml of DMF under N2, 0.27 ml of -4-methoxy-benzyl-thiol was added while stirring. After 0.48 g of solid WIN 63539 was added, the mixture was stirred overnight. The mixture was diluted with CHC13, washed with H20, 10% Na2C0s and brine, dried over Na2O.?. It was filtered and 2 was obtained as a. solid white after the solvent was removed by rotary evaporation. The yield is 80% and the 2 was characterized by TLC and NMR. 1"Example 2 Preparation of 3 and 4: 3 was prepared by a procedure known by the reaction of ethyl propionate of 3-bromo-2-methyl with HS-MBz in sodium ethoxide / ethanol with yields between 60% to 80%. The crude product was used in. the generation in if your subsequent of 4.

Example 3 Preparation of 5: To a solution of 18.2 g of l-amino-2-methyl-2-? Ropanetioi hydrochloride in 150 ml of CH2C12 and 21 ml of trifluoroacetic acid at 0 ° C, was added in the form of drops, a cold solution of 20.1 g of 4-methoxybenzyl chloride in 50 ml of CH2C12. The mixture was stirred at 0 ° C or 1 hour and at room temperature for 3 hours. 30 mL of MeOH was added to the mixture to complete the reaction and all solvents were removed by rotary evaporation. The residue was dissolved in 400 mL of CHC13, washed with saturated NaHCO3 3 x 300 L, NaC03 ai 10%, H20, and brine, dried over Na2SO4. It was filtered and se; obtained 5 as a colorless oil, then the solvent was removed by rotary evaporation. The yield was 95% and the 5 was characterized by TLC and NMR.

Example 4 Preparation of 6: Prepared by the same procedure as _ 5, using L-cysteine ethyl ether hydrochloride. The yield was 95% and the 6 was characterized by TLC and NMR.

Example 5 Preparation of 7: To a solution of 2,6-bis (bromomethyl) pyridine in MeCN, 5 and diisopropyl ether were added. The mixture was refluxed for 3 days and allowed to cool to room temperature. Extraction techniques and chromatography on silica provided 7.

Example 6 Preparation 8: To a solution of 7 in MeCN, diisopropyl ethylamine and ethyl bromoacetate were added, the mixture was heated to reflux temperature overnight and the usual extraction techniques and silica chromatography gave 0.

Example 7 Preparation of 9: To a solution of 3 (5 g) in CHC13, 6.6 TlL of SoCl2 was added dropwise, then the mixture was refluxed for 3 hours. The solvent was removed by rotary evaporation and 50 mL CH2CH2 was added to the residue at 0 ° C. 3.4 ml of Et3N was added slowly and then a solution of 1.1 g of 2,2'-bisaminomethyl thioether in 10 ml of CH2C12 was added dropwise. The mixture was allowed to warm to room temperature and then heated to reflux for 3 hours. It was allowed to cool to room temperature and transferred to a separatory funnel, washed with saturated NaHCO, Na 2 CO 2. at 10%, H20, 1N HCl, H20 and brine, dried over NaSO4. It was filtered and the crude product was obtained after the solvent was removed by rotary evaporation. It was purified by silica chromatography (50%: 50% ethyl acetate rhexanes) and 9 was obtained as "a colorless oil.The yield was 50% and 9 was characterized by TLC and NMR.

Example 8 Preparation of 10: It was prepared and isolated in a serum procedure of 9, using diethylene tpamine. The usual isolation and purification procedures provided a pure product.

Example 9 Preparation of 11: To a solution of 5.3 g 9 in 40 mL of THF, 40 mL of ^ BHS.THF 1N was added. The mixture was heated to reflux for 48 hours and allowed to cool to room temperature. Approximately 10 Mi of 6N NaOH were added to decompose the excess BH3, or the mixture was refluxed for 30 minutes. 2N HCl was added to adjust the pH to a liquid, and all the solvent was removed by rotary evaporation. The residue was dissolved in CHC13, washed with H20, saturated NaHCO3, H20 and brine, dried over Na2SO4. It was filtered and the crude product was purified by chromatography on silica (90%: 10% ethyl acetate: MeOH) and 11 was obtained as a colorless oil. The yield was 50% and 11 was characterized by TLC and NMR.

Example 10 Preparation of 12: was prepared and isolated in a procedure similar to that of 11, using 10 as the initiator material. The usual insulation and. the purification procedures provided a crude product.

Example 11 Preparation 13: To a solution of 2.9 g 11 in 100 mL of MeCN, 0.79 g of diisopropylethylamine and 0.94 g of ethyl bromoacetate were added. The mixture was heated to reflux for 24 hours and allowed to cool to room temperature. The solvent was removed by rotary evaporation and the residue was dissolved in CHC13, washed with H20, saturated NaHCO3, H20, and brine, and dried over Na2SO4. It was filtered and the crude product was purified by chromatography on silica (90% / 10%) ethyl acetate: hexanes). It was dissolved in a mixture of 20 ml of THF and 20 Ml of 5N NaOH. The mixture was refluxed for 1 hour and allowed to cool to room temperature. The pH of the solution was adjusted to 10 with 1N HCl and extracted with CH2C12. The organic phase was washed with H20, 10% Na2CO3, - H20, and brine, dried over Na2SO4. It was filtered and he 13 was obtained as "a white solid, the final yield was 40% and 13 was characterized by TLC and NMR.

Example 12 Preparation of 14: That of 13 was prepared and isolated in a similar procedure, using 12 as the initiator material. The usual isolation and purification procedures provided a pure product.

Example 13 Preparation of 15: To a solution of 8.6 g in 150 mL of CH2C12 at 0 ° C, 5.3 g of thioglycolytic anhydride was added slowly, and the mixture was stirred for 4 hours. It was transferred to a separatory funnel, washed "with H20, 10% Na2CO3, H20 and brine, dried over Na2SO4. It was filtered and 15 was obtained as a colorless oil after the solvent was removed by rotary evaporation. The yield was 90% and 15 was characterized by TLC and NMR.

Example 14 Preparation of 16: Prepared and isolated in a similar procedure as that of 15, using aminoprotected iminodiacetic anhydride, as the initiator material. The usual isolation and purification procedures provided a pure product.

Example 15 Preparation of 17: To a solution of 6.5 g of 15 in 150 L of CHC13, 4.4 g of solid carbonyldiimidazole was added slowly, and the mixture was stirred for 30 minutes. Then a solution of 5.7 g of 6"in 50 L of CHC13 was added, and the mixture was stirred during the no-che. It was transferred to a separatory funnel, washed" with H20, 1N HCl, H20 Na2C03 at 10 ° C. %, H20 and brine, dried over Na2SO4. It was filtered and the crude product was purified by silica chromatography (90%: 10 &ethyl acetate / hexane) The yield was 60% and 17 was characterized by TLC and NMR.

Example 16 Preparation of 18: That of 17 was prepared and isolated from a similar procedure, using 16 as the initiator material. The usual isolation and purification procedures provided a pure product.

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, the content of the following is claimed as property.

Claims (24)

1. - - CLAIMS A compound of formulas III, V, VI O VII (where each n, which can be the same or different, is an integer 2, 3 ^ or 4). - - characterized in that each R, which may be the same or different, is H or a protective thiol group; X is O, S, NR4 or a substituted phosphorus; X * is a carbon attached to a heteroatom ring, optionally substituted by a group R5. Each R4, which may be the same or different, is H or CH3; R3 is hydrogen or optionally substituted alkyl, aryl, alkaryl or aralkyl; and R6 is H or a functionalized alkyl; or a salt or complex thereof.
2. 2. A complexing compound of formula I R3S (CR1 *) "NCR2) i (CR)" X (I) characterized by each nr aue It may be the same or different, it is an integer of 2, 3 or 4 (preferably 2); each i, which can be the same or different, represents 0 or 1; each R3, which may be the same or different, is H or a protective thiol group, preferably a protecting group; X is O, - - each R, which may be the same or different, is hydrogen or an optionally substituted organic group; each R1, which may be the same or different, is a hydrogen group or an optionally substituted organic group, or a CR12 portion may represent one carbonyl group or two, three or four R ^ 's are two different carbons together with those carbons and any intervening atom may represent a homocyclic or saturated heterocyclic ring or a salt or complex former thereof, wherein optionally at least a portion of R1, R2, R3 and R4 is directly or indirectly coupled to a portion of the vector, and where the two groups (CR12) n between the N (R) X and portions X are groups (CH2) not groups (CR12) n (CH2) n_! Where the CR12 portions are attached to the nitrogens N (R2) i.
3. 3. A compound as claimed in claim 2, characterized in that at least one portion CR12 is preferably CH2 or CH (CH3), or a salt or complex "" thereof. - - Four .
4. A compound as claimed in claim 2 or claim 3, characterized in that n is 2, and each R 3 is independently a protective thiol group, or a salt or complex forming 17"itself.
5. 5. A compound as claimed in any one of claims 2 to 4, characterized in that it comprises zero, one or two heterocyclic rings that incorporate nitrogen, oxygen or sulfur rings of N (R2) _, and X portions.
6. 6. A compound as claimed in any one of claims 2 to 5, characterized in that the groups (CR12) adjacent to a group CR12 that are part of a cyclic group by themselves, are part of a cyclic group or are CH or CH2 groups .
7. 7. A compound as claimed in any one of claims 2 to 6, characterized in that the CR12 portions adjacent to the - SR groups are CH, or CR52 groups, in which each R5 is independently an alkyl group.
8. 8. A compound as claimed in any one of the preceding claims, with metal-forming atoms, at least one metal ion or a complex ion.
9. 9. A compound as claimed in claim 8, characterized in that said metal ion is selected from radionuclides, paramagnetic ions, fluorescent ions, heavy metal ions and ions of clusters.
10. 10. A compound as claimed in claim 8, characterized in that said metal ion is selected from ions of Ag, At, Au, Bi, Cu, Ga, Ho, In, Lu, Pb, Pd, Pm, Pr, Rb , Re, Rh, Se, Sr, Te, TI, Y, and Yb. - -
11. 11. A compound as claimed in claim 9, characterized in that the radionuclide is selected 90Y, 99mTC, X11ln, 47Sc, 67Ga, 51 Cr, 177mSn, 6"7'.Cu, 167 Tm, 97 Ru, 186 Re, 177 Lu, 199 Au,: 03 Pb and
12. 12. A compound as claimed in claim 9, characterized in that said paramagnetic metal ion is selected from transition metal ions and lanthanide metals, preferably metals having atomic numbers of 21-29, 42, 43, 44 or 57-7" .
13. 13. A compound as claimed in any one of the preceding claims, characterized in that it is directly or indirectly coupled to a portion of a vector capable of having targets of particular receptors, organs, tissues or body compartments.
14. 14. A compound as claimed in claim 13, characterized in that said portion of the vector is selected from proteins, antibodies, antibody fragments, - - oligopeptides, hormones, polyalkylene oxides, and famraceutics.
15. 15. A pharmaceutical composition characterized in that it comprises an effective amount of a compound as defined in any one of claims 1 to 14, or a salt or forming complex thereof, together with at least one pharmaceutically effective carrier or excipient.
16. 16. The use of a compound as defined in any one of claims 1 to 14, or a salt or complexing thereof, for the manufacture of a contrast medium for use in a diagnostic method involving the administration of said contrast medium to an animated subject and the generation of an image of at least part of said subject.
17. 17. The use of a compound as defined in any one of claims 1 to 14, or a salt or complex-forming thereof, for the preparation of a therapeutic agent, preferably a radiopharmaceutical "
18. 18. Use as claimed in claim 17 in the manufacture of a therapeutic agent for use in tumor therapy.
19. 19. One method a method for the generation of an animated image of a human or non-human animal subject (preferably a mammal or a bird) that involves the administration of a contrast agent to said subject, for example, in the vascular system or the gastrointestinal tract , and the generation of an image of at least a part of said subject to which said contrast agent has been distributed, for example by means of X-rays, MR, ultrasound, scintigraphic, PET, SPECT, electrical impedance, image-forming modalities of light or magnetometric, characterized in that as said contrast agent a compound is used as defined in any one of claims 1 to 14, or a salt or complex-forming thereof. - -
20. 20. A method of treating a human or non-human animal subject (preferably a mammal or a bird) that involves administering a contrast agent to said subject, characterized in that said compound is a compound as defined in any one of claims 1 to 14, or a salt or complex former thereof.
21. 21. A process for the preparation of a complex of a complex former optionally coupled to a vector according to any one of claims 1 to 7, characterized in that said process comprises the metal atoms in a complex former optionally coupled to a vector of according to any one of claims 1 to 7, with a diagnostically or therapeutically effective metal ion or an ion of a metal-containing complex.
22. 22. The use of a compound of formula IV - - (where each R, which can be the same or different, is H or a protective thiol group, each R4, can be the same or different, is H or CH3, R5 is hydrogen or alkyl, aryl, alkaryl or aralkyl optionally substituted, and R6 is H or functionalized alkyl, or a salt or complex-forming thereof, for the manufacture of a contrast medium for use in a diagnostic method involving the administration of said contrast medium to an animate subject and the generation of an image of at least a part of said subject. -2. 3.
23. A method for the generation of an animated image of a human or non-human animal subject that involves the administration of a contrast agent to said subject, and the generation of an image of at least a portion of said subject to which - - said contrast agent has been distributed, for example by means of X-rays, MR, ultrasound, scintigraphic, PET, SPECT, electrical impedance, light or magnetometric image-forming modalities, characterized in that said contrast agent is used as a compound of formula IV as defined in claim 22, or a salt or forming complex thereof.
24. 24. The use of a compound of formula IV as defined in claim 22, or a salt or complexing thereof, for the manufacture of a therapeutic agent, preferably a radiopharmaceutical, for use in tumor therapy. SUMMARY OF THE INVENTION The invention provides a complex forming compound of formula (I): R3S (CR1?) "N (R2) i (CR12) nX (CRl2) BN (Ri) iCCR1;,) ^ Sll3 < ? > where each n, which may be the same or different, is an integer of 2, 3 or 4 (preferably 2); each i, which can be the same or different, represents 0 or 1; each R3, which may be the same or different, is H or a protective thiol group, preferably a protecting group; X is 0, S, N, NR4, or a substituted phosphorus (for example oxo substituted phosphorus), preferably S or N; each R2, which may be the same or different, is hydrogen or an optionally substituted organic group; each R1, which may be the same or different, is a hydrogen group or an optionally substituted organic group, or a CR12 portion ~~ may represent one carbonyl group or two, three or four R1s are two different carbons together with those carbons and any intervening atom, may represent a homocyclic- or saturated heterocyclic ring or a salt or complex-forming thereof, wherein optionally at least a portion of R1, R2, R3 and R4 is directly or indirectly coupled to a portion of the vector.